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Biological Research

versão impressa ISSN 0716-9760

Biol. Res. v.35 n.1 Santiago  2002

http://dx.doi.org/10.4067/S0716-97602002000100004 

Glucose transporters: expression, regulation and cancer

RODOLFO A. MEDINA1 and GARETH I. OWEN2


1Laboratorio de Biologia Celular y Molecular, MIFAB, Universidad Nacional Andres Bello, Avenida Republica 217, Piso 4, Santiago, Chile
2Departamento de Endocronologia, Pontificia Universidad Católica de Chile, Alameda 340, Santiago, Chile

Corresponding author: Rodolfo A. Medina, Laboratorio de Biologia Celular y Molecular, Universidad Nacional Andres Bello, Avenida Republica 217, Piso 4, Santiago, Chile. Phone: 56-2-661 8419. Fax: 56-2-698 0414. e-mail: rmedina@abello.unab.cl

Received: February 01, 2002. Accepted: April 5, 2002

ABSTRACT

Mammalian cells depend on glucose as a major substrate for energy production. Glucose is transported into the cell via facilitative glucose transporters (GLUT) present in all cell types. Many GLUT isoforms have been described and their expression is cell-specific and subject to hormonal and environmental control. The kinetic properties and substrate specificities of the different isoforms are specifically suited to the energy requirements of the particular cell types. Due to the ubiquitousness of these transporters, their differential expression is involved in various disease states such as diabetes, ischemia and cancer.

The majority of cancers and isolated cancer cell lines over-express the GLUT family members which are present in the respective tissue of origin under non-cancerous conditions. Moreover, due to the requirement of energy to feed uncontrolled proliferation, cancer cells often express GLUTs which under normal conditions would not be present in these tissues. This over-expression is predominantly associated with the likelihood of metastasis and hence poor patient prognosis. This article presents a review of the current literature on the regulation and expression of GLUT family members and has compiled clinical and research data on GLUT expression in human cancers and in isolated human cancer cell lines.

Key terms: GLUT, glucose transporters, expression, cancer, estrogen, progesterone, cell lines

INTRODUCTION


Most mammalian cells depend on a continuous supply of glucose not only as a precursor of glycoproteins, triglycerides and glycogen but also as an important source of energy by generating ATP through glycolysis. Glucose is a hydrophilic compound; it cannot pass through the lipid bilayer by simple diffusion, and therefore requires specific carrier proteins to mediate its specific transport into the cytosol. There is an energy-dependent Na+/glucose co-transporter in the polarized epithelial cells in the lumen of small intestine and in the proximal tubules of the kidney. Exclusively in the aforementioned cells this protein uses the movement of Na+ down its electro-chemical gradient to drive the uptake of glucose.

A ubiquitous glucose transport system also exists. All mammalian cells contain one or more members of the facilitative glucose transporter gene family named GLUT (Table 1). These transporters have a high degree of stereoselectivity, providing for the bidirectional transport of substrate, with passive diffusion down its concentration gradient. GLUTs function to regulate the movement of glucose between the extracellular and intracellular compartments maintaining a constant supply of glucose available for metabolism.

As any cell divides and grows the demand for energy increases, this is no less true for cancer cells. Normal mammalian cells use oxygen to generate energy from glucose, and other substrates, through oxidative phosphorylation. Although tumors induce formation of new blood vessels to deliver nutrients and oxygen to the growing tumor, angiogenesis does not keep pace with the growth of the neoplastic cells. This results in large hypoxic areas throughout the tumor.

To form a three-dimensional multicellular mass, tumor cells must change their metabolism in order to survive and grow under these ischemic conditions (Dang & Semenza, 1999). Tumor cells in these areas are not killed by ionizing radiation, which depends on oxygen, or by chemotherapeutic drugs, which do not reach these regions. A characteristic feature of these ischemic conditions is the production of large amounts of lactic acid from glycolysis in the presence of reduced oxygen concentrations (Warburg, 1956). This is accompanied by an increased rate of glucose transport (Pedersen, 1978: Birnbaum et al, 1987). We have shown that lactate causes translocation of GLUT1 and GLUT4 to the plasma membrane in isolated perfused hearts (Medina et al, 2002). It is possible that the lactate acid build-up in tumors is involved in translocation of the transporters to the plasma membrane which in turn causes an increase in glucose utilization by these cells. This demand for energy is satisfied by an increased sugar intake which is accomplished by an increase in glucose transporter expression and an increase in the translocation of the transporter to the plasma membrane.

 

GLUT STRUCTURE AND FUNCTION

Localization and structure


The GLUTs are intrinsic membrane proteins which differ in tissue-specific expression and response to metabolic and hormonal regulation (James et al, 1994; Mueckler, 1994; Stephens & Pilch, 1995). Many different isoforms of GLUT have been identified (Table 1); all appear to share a common transmembrane topology, having a large (50% of protein mass), highly conserved (97%), transmembrane domain, with a less conserved, grossly asymmetric, non-membrane, cytoplasmic and exoplasmic domains (Jung, 1998). The transmembrane domain is composed of twelve membrane-spanning-helices, containing a water-filled pathway through which the substrate moves (Lachaal et al, 1996; Zheng et al, 1996). The cytoplasmic domain contains a short N-terminal segment, a large cytosolic loop and a large C-terminal segment. The exoplasmic domain contains a large loop bearing a single N-linked oligosaccharide moiety. The fact that isoform-specific amino acid sequences are found at the cytoplasmic and exoplasmic domains indicates that they are responsible for tissue-specific regulation of transporter function. The fact that the transmembrane domain primary structure is largely conserved suggests that the glucose channel is basically identical in structure among the isoforms of this family.

TABLE 1
Tissue-specific expression of the GLUT family members.


Protein Alias Expression Function Reference

GLUT1  

All tissues (abundant in brain
and erythrocytes)

Basal uptake Mueckler et al, 1985
GLUT2  

Liver, pancreatic islet cells,
retina

Glucose sensing

Fukumoto et al, 1988
Watanabe et al, 1999
GLUT3   Brain Supplements GLUT1 in
tissues in tissues with
high energy demand
Kayano et al, 1988
GLUT4   Muscle, fat, heart Insulin responsive Fukumoto et al, 1988
GLUT5   Intestine, testis, kidney,
erythrocytes
Fructose transport Kayano et al, 1990,
Concha et al, 1997
GLUT6 GLUT9 Spleen, leukocytes, brain   Doege et al, 2000
GLUT7   Liver   Joost&Thorens, 2001
GLUT8 GLUTX1 Testis, brain   Doege et al, 2000a
GLUT9 GLUTX Liver, kidney   Phay et al, 2000
GLUT10   Liver, pancreas   McVie-Wylie et al, 2001
GLUT11 GLUT10 Heart, muscle   Doege et al, 2001
GLUT12 GLUT8 Heart, prostate   Rogers et al, 1998
pseudogene GLUT6     Kayano et al, 1990

Physiological function


The physiological function of GLUT transporters depend on their kinetic and substrate specificities. Several studies have examined the kinetic properties of the isoforms. However, the facts that glucose is rapidly metabolized and that transport is not always rate-limiting, means that nonmetabolizable glucose analogues, such as fluoro-deoxyglucose (FDG), 2-deoxyglucose (DG) and 3-O-methylglucose, have to be used as glucose tracers. Results of transport assays, under equilibrium exchange conditions, show an apparent Km for 3-O-methylglucose transport by GLUT1 of 16.9-26.2 mM (Gould et al, 1991; Nishimura et al, 1993). Under the same conditions GLUT4 has a Km of 1.8-4.8 mM (Keller et al, 1989, Nishimura et al, 1993) and GLUT3 has a Km of 10.6 mM (Gould et al, 1991). This means that GLUT3 and GLUT4 have a higher affinity for glucose than GLUT1, ensuring that glucose transport will be maximal in tissues containing these isoforms even when glucose concentrations are low. This is particularly important for the brain, which expresses GLUT3, and relies on glucose as its only source of energy.

GLUT2 has a very low affinity for glucose with a Km for 3-O-methylglucose of 40 mM (Gould et al, 1991). Since normal circulating glucose concentration is 3.9-5.6 mM, the rate of transport will be directly proportional to glucose concentration. Therefore, in the postprandial state, when circulating glucose levels are high, there is a net flux of glucose into hepatocytes and pancreatic ß-cells. In contrast, when circulating glucose levels are low, intracellular glucose concentration will increase as a result of glycogenolysis and gluconeogenesis. When the intracellular glucose concentration exceeds the plasma concentration GLUT transports glucose from the liver into the circulation. GLUT2 also functions as a low-affinity fructose transporter, which is consistent with the liver being the primary site for fructose metabolism (Gould et al, 1991). GLUT2 is further involved in the anterior transport of glucose supplied by choroidal circulation from the early stages of retinal development (Watanabe et al, 1999).

The localization, expression and regulation of the GLUT family are tissue and often cell-specific. New GLUT isoforms are continually being discovered and characterized in various cell types. Their involvement in disease states is also continually under review. In cancer cells, which have broken free from the normally tight global regulation, aberrant expression of the GLUT family members provides the energy source required for further uncontrolled proliferation and metastasis. As every cell contains the genes for each GLUT family member we observe in cancer cells the expression of certain GLUT isoforms which, under normal conditions, would never have been expressed in these tissues (Table 2 and 3). The review will place emphasis on the best described models of GLUT expression and regulation. These are GLUT1 and GLUT4 in adipose and muscle tissue. GLUT1 is thought to play a constitutive role, and is responsible for basal glucose uptake. GLUT4 is the inducible transporter and is classically referred to as the "insulin-responsive" transporter. This nomenclature has arisen due to its translocation from the intracellular membrane compartment to the plasma membrane, which was originally described in response to insulin (Slot et al, 1991; Kraegen et al, 1993).

As well as transporting hexoses, the glucose transporters have also shown to be involved in the transport of ascorbic acid. Although in specialized cells vitamin C can be transported directly through a sodium ascorbate cotransporter, in the majority of cells vitamin C entry is mediated by glucose transporters in the form of dehydroascorbic acid (Vera et al, 1993; Agus et al, 1997).

This compound is then reduced intracellularly to ascorbic acid. Many human tumors have been demonstrated to contain high concentrations of ascorbic acid and thus the glucose transporters may play a role in the intracellular availability of ascorbic acid in cancer cells (Agus et al, 1999)

 

TABLE 2

The Expression of GLUT1 in Human Cancer
Association refers to an association between Glut1 with metastasis and or poor prognosis of the cancer. NR refers to
data Not Reported by the authors. Expression refers to the level Glut1 in relation to relevant non-cancerous tissue.


Cancer Type Expression Association Source

Bladder

Over-expressed Associated Chang et al, 2000

Bladder

Over-expressed Associated Younes et al, 2001
Brain Over-expressed Associated Boado et al, 1994
Brain Reduced Not Associated Nagamatsu et al, 1993
Brain (Choroid Plexus) Reduced Not associated Kurosaki et al, 1995
Breast Over-expressed Associated Alo et al, 2001
Breast Over-expressed Associated Zimmerman et al, 2001

Breast

Over-expressed Associated Younes et al, 1995
Breast Over-expressed Associated Brown et al, 1993

Breast

Over-expressed NR Binder et al, 1997

Cervical

Over-expressed Associated Airley et al, 2001

Colorectal

Over-expressed Associated Sakashita et al, 2001

Colorectal

Over-expressed Associated Younes et al, 1996
Colorectal Over-expressed Associated Haber et al, 1998
Cutaneous Basal Cell No Change NR Baer et al, 1997
Cutaneous Squamous Cell Over-expressed NR Baer et al, 1997

Embrionic

Over-expressed NR Loda et al, 2000
Esophageal Over-expressed NR Younes et al, 2000a

Esophageal

Over-expressed Not Associated Younes et al, 2000b
Gastric Over-expressed Associated Kawamura et al, 2001
Gastric Over-expressed Associated Noguchi et al, 1999
Head and Neck Over-expressed NR Reisser et al, 1999
Head and Neck Over-expressed Not associated Mellanen et al, 1994
Head and Neck Over-expressed Associated Reisser et al, 1999

Leiomyosarcomas

Over-expressed Associated Rao et al, 1999
Lung Reduced Not associated Nigashi et al, 2001
Lung Over-expressed Not associated Kurata et al, 1999
Lung Over-expressed Associated Younes et al, 1997
Lung Over-expressed Associated Ogawa et al, 1997
Lung Over-expressed Associated Brown et al, 1999

Lung

Over-expressed NR Ito et al, 1998
Lung (Brain metastsis) Reduced NR Zhang et al, 1996
Ovarian Over-expressed Associated Cantuaria et al, 2001
Pancreatic Over-expressed NR Reske et al, 1997

Pancreatic (islet)

Over-expressed NR Boden et al, 1994
Penile Over-expressed NR Moriyama et al, 1997
Thyroid Over-expressed Associated Lazar et al, 1999
Thyroid Over-expressed NR Haber et al, 1997
Uterus Over-expressed NR Wang et al, 2000
Vascular (Hemangioma) Over-expressed NR North et al, 2001

GLUT PHYSIOLOGY

Adipose and muscle tissue

One of the most important, and well established, models of GLUT regulation is the stimulation of GLUT expression and translocation in adipose and muscle tissue by insulin (Birnbaum, 1992; James & Piper, 1994; Slot et al, 1991). It is this process that provides the regulation of whole-body glucose homeostasis and, when dysfunctional, plays a vital role in diabetes mellitus. GLUT4 is almost completely responsible for insulin-stimulated glucose transport. In rat adipocytes, the most studied cell system for insulin action on glucose transport, more than 95% of GLUT4 and 30-40% of GLUT1 is associated with intracellular membranes, and are thus non-functional. These GLUTs are translocated to the plasma membrane in response to insulin, where they are able to facilitate the transport of substrate (Suzuki & Kono, 1980). GLUT4 is constantly recycled between the plasma membrane and intracellular storage pool with two discrete first-order rate constants, one for internalization (kin) and one for externalization (kex). Insulin causes transporter translocation by reducing kin and increasing kex approximately 3-fold each (Jhun et al, 1992). Impaired GLUT activity is in part responsible for insulin resistance in human diabetes and obesity (Ismail-Beigi, 1993).

Heart

The rate of glucose utilization in the rat heart is greater than in many tissues such as skeletal muscle, adipose and lung (James et al, 1985). Cardiac muscle glucose transport and utilization is vital for normal function, a fact illustrated in GLUT4 cardiac knockout mice which show cardiac hypertrophy and other major morphologic heart changes (Katz et al, 1995). Moreover, a high rate of cardiac glucose metabolism becomes crucial during ischemia when oxidative phosphorylation is limited. Under basal conditions glucose transport is the rate limiting step in glucose metabolism, however, the element of control shifts to phosphorylation by hexokinase in the presence of insulin (Kashiwaya et al, 1994).

TABLE 3

The Expression of GLUT2-5 in Human Cancer
Association refers to an association between GLUT2-5 with metastasis and/or poor prognosis of the cancer. NR refers to
data Not Reported. Expression refers to the level GLUT2-5 in relation to relevant non-cancerous tissue.


Cancer Type

Glut Expression Association Source

Gastric

Glut 2 Over-expressed Associated Noguchi et al, 1999

Pancreatic

 

Glut 2 Reduced Not Associated Seino et al, 1993
Brain Glut3 No Change NR Nagamatsu et al, 1993
Brain Glut 3 Over-expressed Associated Boado et al, 1994

Breast

Glut 3 Over-expressed NR Binder et al, 1997
Gastric Glut 3 Over-expressed NR Noguchi et al, 1999

Gastric

Glut 3 Over-expressed NR Younes et al, 1997b
Head and Neck Glut 3 Over-expressed NR Reisser et al, 1999
Head and Neck Glut 3 Over-expressed Not Associated Mellanen et al, 1994

Lung

Glut 3 Over-expressed Associated Kurata et al, 1999
Lung Glut 3 Over-expressed NR Ito et al, 1998

Lung

Glut 3 Over-expressed Associated Younes et al, 1997a
Lung Glut 3 Over-expressed NR Younes et al, 1997a

Meningiomas

Glut 3 Over-expressed NR Glick 1993

Ovarian

 

Glut 3 Over-expressed NR Younes et al, 1997b

Breast

Glut 4 Over-expressed NR Binder et al, 1997

Gastric

Glut 4 Over-expressed NR Noguchi et al, 1999

Lung

Glut 4 Over-expressed NR Ito et al, 1998

Pancreatic

 

Glut 4 Reduced Not Associated Reske et al, 1997
Lung Glut 5 Over-expressed Associated Kurata et al, 1999

There are two main glucose transporters present in cardiac tissue. Under un-stressed conditions approximately 60-70% of GLUT1 and 10-20% of GLUT4 is localized in the plasma membrane (Zorzano et al., 1997). In cardiomyocytes, GLUT4 and GLUT1 account for approximately 60% and 40% respectively, of total glucose carriers (Fischer et al, 1997). A number of different stimuli, such as ischemia, insulin and lactate, have been shown to cause translocation of GLUT1 and GLUT4 to the plasma membrane (Brosius et al, 1997; Egert et al, 1999; Montessuit et al, 1998, Fuller et al, 2001; Medina et al, 2002). These effects may be crucial in the overall metabolism of glucose since, as mentioned above, under many conditions; transmembrane transport is the limiting step in glucose breakdown in the heart (Doenst & Taegtmeyer, 1998; Manchester et al, 1994; Nguyen et al, 1990). In addition to increased translocation of GLUT4 in response to acute myocardial ischemia, chronic ischemia increases GLUT1 protein content by enhancing GLUT1 mRNA expression (Brosius et al, 1997).

Fasting and diabetes cause a repression of cardiac GLUT1 and GLUT4 protein levels in the rat heart (Kraegen et al, 1993) and cardiac sarcolemmal vesicles from diabetic rats show decreased glucose transport (Garvey et al, 1993). These results suggest a decrease in glucose transporter number at the cell surface and indicate that both fasting and diabetes alter the expression and distribution of glucose transporters. Therefore, it is possible that GLUT depletion and diminished glucose transport across the cell surface of cardiomyocytes in diabetes could limit glucose availability and lead to myocardial dysfunction.

Brain

Many tissues types can utilize a variety of substrates, such as glucose, lactate and fatty acids, as an energy source. In contrast, the adult central nervous system relies on glucose as its sole source for ATP production. In order for glucose to reach neurons within the brain it must first cross the endothelium of the blood brain barrier into the interstitial space. From this compartment glucose must be transported across the neuronal plasma membrane using the ubiquitous GLUT1 and GLUT3 isoforms. Brain GLUT1 is a multiple-molecular-weight species ranging between 45-55 KDa (Olson & Pessin, 1996). The larger-molecular-weight species are present in microvessels (Maher et al, 1994), the smaller species are present in vessel-free preparation on brain membranes (Pardridge et al, 1990) and an intermediate species is present in the choroid plexus (Kumagai et al, 1994). The differences in molecular weight are due to differences in N-linked glycosylation. The functional effect of the different glycosylation states is not clear although there is evidence suggesting that they are involved in GLUT1 trafficking (McMahon et al, 2000) and substrate affinity (Onetti et al, 1997). GLUT3 is highly expressed in the brain (Nagamatsu et al, 1992), specifically in neurons (Maher et al, 1993). Its relatively low Km indicates that glucose transport via GLUT3 is near maximal at normal plasma glucose concentrations (Gould et al, 1991). GLUT1 and GLUT3 expression is regulated by developmental stage and by metabolic state. Fetal and neonatal rat mainly express GLUT1 in all brain related cell types, but neurons change to the expression of GLUT3 at about 10 days after birth (Nagamatsu et al, 1994). GLUT3 mRNA levels are up-regulated by hypoglycemia in mouse brain in an apparent protective mechanism against energy depletion (Nagamatsu et al, 1994a). In accordance with the neural tissue having a preference for GLUT3 mediated glucose uptake, it is the detection of immunoreactive GLUT3, but not GLUT1, in the high grade gliomas which suggests that GLUT3 isoform may be the predominant glucose transporter in highly malignant glial cells of human brain (Boado et al, 1994), (Table 2 and 3). The same observation is apparent in the choroid plexus where GLUT1 is down-regulated while GLUT3 levels remain unchanged (Kurosaki et al, 1995). As an example that each cancer is different, Boado and colleagues (1994) observed that GLUT1 was over-expressed in malignant glial cells. Although GLUT1 is the consistently over-expressed isoform, the presence of GLUT3 tends to be a major factor in tumour progression. GLUT3 over-expression in lung cancer cells confers a higher probability of metastasis and thus worse prognosis than GLUT1 over-expression alone (Younes et al, 1997a ,b). In accordance with this report, Zhang and colleagues (1996) observed reduced GLUT1 expression in lung cancer cells that metastasized to the brain (Table 2)

Liver and pancreatic cells

GLUT2 is primarily expressed in hepatocytes and pancreatic-cells with lower levels expressed in kidney and intestines. GLUT2 is a low-affinity receptor with a high turnover rate (Gould et al, 1991). These kinetic properties allow GLUT2 to function in the liver where glucose transport must not be rate limiting for influx or efflux. When circulating glucose levels are high there needs to be net hepatic uptake as the intracellular glucose is metabolized or converted into glycogen. Conversely, when glucose levels are low, the liver needs to export glucose to the plasma. This is achieved by GLUT2 coupled with the regulated phosphorylating activity of hexokinase IV. Thus, during periods of glycogen synthesis hexokinase IV is up-regulated and increases the formation of glucose-6-phosphate (Magnuson et al, 1989). This provides the precursor for glycogen synthesis and glycolysis and maintains intracellular glucose concentration low, which in turn drives the influx of glucose. In contrast, during glycogenolysis and gluconeogenesis, hexokinase IV is down-regulated, intracellular glucose concentration becomes greater than in the plasma and there is a net efflux of glucose.

In order to regulate insulin secretion, pancreatic-cells need to be highly sensitive to changes in plasma glucose concentrations. Therefore, a low-affinity transporter, such as GLUT2 will not be saturated at physiological levels and glucose flux will be proportional to plasma glucose concentration. As in the liver, hexokinase regulates the entry of glucose into the glycolytic pathway and, along with GLUT2, plays a role in glucose sensing by ß-cells (Hughes et al, 1992; German, 1993; Heimberg et al, 1993).

Interestingly in pancreatic cancer cells it is GLUT1 (Boden et al, 1994) which is over-expressed while GLUT2 (Seino et al,1993) and GLUT4 (Reske et al, 1997) expression are reduced, suggesting GLUT1 is the predominant mechanism of glucose transport in these cancers. Despite this, several pancreatic cell lines have been isolated which express GLUT2 (see Table 4). To date, in liver derived (hepatoma) cancer cell lines, only GLUT1 has been demonstrated to be present.

Intestine and kidney

The small intestine and kidney express the isoforms GLUT1, GLUT2, GLUT3, GLUT5 and the Na+-dependent glucose transporter. GLUT2 is the primary isoform responsible for transport across the basolateral membrane of intestinal epithelial cells (Thorens et al, 1990) while GLUT5 mediates fructose uptake from the intestinal lumen and efflux from the intestinal epithelia (Blakemore et al, 1995). GLUT2 can also transport fructose but with a six-fold lower affinity than GLUT5 (Colville et al, 1993). Human digestive tract cancers (gastric and colorectal) show a distribution of GLUT over-expression with GLUT1, GLUT 2 and GLUT4 over-expressed. As a means of studying GLUT signaling, numerous gastric and colorectal cell lines have been established which express one or more of the isoforms GLUT 1-GLUT5 (Table 4).

TABLE 4

GLUT Expression in Human Cancer Cell Lines.
The GLUT family members reported here refer only to the glucose transporters reported in the corresponding papers
and thus do not necessarily suggest over-expression of these transporters in relation to non-cancerous tissue of
origin or the absence of other family members in these cell lines.


Tissue Origin Denomination Glut Expression Source

Acetabulum HT-1080 Glut 1 (presumed) Waki et al, 1998

Bone

HOS Glut 1 (presumed) Waki et al, 1998

Brain

Hs 683 Glut 1 (presumed) Waki et al, 1998
Brain H4 Glut 1 (presumed) Waki et al, 1998
Brain A-172 Glut 1 (presumed) Waki et al, 1998

Breast

MDA-MB-231 Glut 1, 3 Aloj et al, 1999

Breast

MDA-MB-435 Glut 1, 2, 5 Grover-McKay et al, 1998

Breast

MDA-MD-231 Glut 1 Grover-McKay et al, 1998

Breast

13762 Glut 4 Ara et al, 1998
Breast MDA-468 Glut 1, 2, 5 Zamora-leon et al, 1996
Breast T47D Glut 1 Aloj et al, 1999
Breast MCF-7 Glut 1, 3 Aloj et al, 1999

Breast

MCF-7 Glut 1 Gover-McKay et al, 1998

Breast

MCF-7 Glut 1, 2, 5 Zamora-Leon et al, 1996
Breast T47D Glut 1, 2, 3, 4 Rivenzon-Segal et al, 2000
Cervical HeLa Glut 1 Kitagawa et al, 1995
Choriocarcinoma BeWo Glut 1, 3 Ogura et al, 2000
Choriocarcinoma JEG-3 Glut 1, 3 Hahn et al, 1998
Choriocarcinoma JAr Glut 1, 3 Clarson et al, 1997
Choriocarcinoma BeWo Glut 1, 5 Shah et al, 1999
Colorectal CaCo-2 (PD7) Glut 5 Mesonero et al, 1995

Colorectal

Caco-2 Glut 1, 3, 5 Aloj et al, 1999
Colorectal Caco-2 Glut 5 Matosin-Matekalo et al, 1999
Colorectal LS180 Glut 1 Waki et al, 1998

Colorectal

LS180 Glut1 Fujibayashi et al, 1997

Colorectal

Caco-2 Glut 1, 3, 5 Harris et al, 1992
Colorectal Caco-2 Glut 2, 5 Brot-Laroche 1996

Colorectal

Caco-2 (clones) Glut 1, 2, 3, 5 Mahraoui et al, 1994
Colorectal Caco2 Glut 1 (presumed) Waki et al, 1998
Colorectal WiDr Glut 1 (presumed) Waki et al, 1998
Colorectal LS 174T Glut 1 (presumed) Waki et al, 1998

Epidermoid

A431 Glut 1 Aloj et al, 1999
Gastric MKN45 Glut 1, 4 Noguchi et al, 1999
Gastric MKN 28 Glut 4 Noguchi et al, 1999
Gastric STKM1 Glut 4 Noguchi et al, 1999
Insulinoma CM Glut 1, 2 Baroni et al, 1999
Leukemia K562 Glut 1 Ahmed et al, 1999
Leukemia U937 Glut 1 Ahmed et al, 1999

Leukemia

U937 Glut 1, 5 Rivas et al, 1997
Leukemia HL60 Glut 1 Ahmed et al, 1999

Leukemia

HL60 Glut 1 Chan et al, 1999
Leukemia HL60 Glut 1, 5 Vera et al, 1994, Rivas et al, 1997
Leukemia K562 Glut 1 Cloherty et al, 1996
Leukemia Jurkat Glut 1 Berridge et al, 1996
Leukemia ACH2 Glut 1 Rivas et al, 1997
Leukemia 3BH9 Glut 1 Rivas et al, 1997
Leukemia U1 Glut 1, 5 Rivas et al, 1997
Leukemia CEM Glut 1 Rivas et al, 1997
Leukemia H9 Glut 1 Rivas et al, 1997
Liver Hep3B Glut 1 Iliopoulos et al, 1996
Liver HepG2 Glut 1 Younes et al, 2000
Liver HepG2 Glut 1 Aloj et al, 1999

Nasal septum

RPMI 2650 Glut 1 (presumed) Waki et al, 1998
Oral OSCCs Glut 1, 2, 4 Fukuzumi et al, 2000
Ovarian HTB 771P3 Glut 1 Clavo et al, 1995
Ovarian A2780S Glut 1 Cantuaria et al, 2000
Ovarian A2780cP Glut 1 Cantuaria et al, 2000

Pancreatic

beta-TC6-F7 Glut 2 Knaack et al, 1994
Pancreatic HP-62 Glut 2 Papadopoulos et al, 1996
Renal 786-0 Glut 1 Iliopoulos et al, 1996
Retinoblastoma Y79 Glut 1, 4 Tsukamoto et al, 1997
Retinoblastoma WERI-Rb1 Glut 1, 3 Tsukamoto et al, 1997

Rhabdomyosarcoma

RD (18) Glut 1, 3, 4 Ito 2000
Skin HTB 63 Glut 1 Clavo et al, 1995
Skin A-375 Glut 1 (presumed) Waki et al, 1998

SIGNALING PATHWAYS IN GLUT TRANSLOCATION

Insulin

Studies in adipose, heart and skeletal muscle have shown that insulin-induced translocation of GLUT4 is mediated by phosphatidylinositol-3-kinase (PI3K), as has been shown using wortmannin, a potent inhibitor of the enzyme (Lee et al, 1995).

One possible mechanism for GLUT4 translocation is through the activation of protein kinase Bb/Akt2, a downstream target of PI3K (Table 5). Intracellular GLUT4-containing vesicles have a high basal level of PI4K activity. Insulin stimulation targets PI3K to these vesicles leading to the accumulation of these enzymes which act as docking sites for the recruitment and activation of Akt2. Akt2 phosphorylates vesicular proteins, including GLUT4, which causes the dissociation of the vesicles from an intracellular anchor and subsequent fusion with the plasma membrane (Kupriyanova & Kandror, 1999). Although the consensus is that PI3K is involved in insulin-stimulated GLUT4 translocation, it is not clear whether other parallel pathways exist. There is evidence that the GTP-binding protein Gq can couple to GLUT4 translocation in adipocytes. This pathway is PI3K independent, requires tyrosine kinase activation and its inhibition prevents insulin-stimulated GLUT4 translocation (Kanzaki et al, 2000) (Table 5). This data suggests that insulin causes GLUT4 translocation though at least two independent pathways in adipocytes.

Ischemia and hypoxia

Ischemia, hypoxia and contraction cause GLUT4 translocation through a PI3K independent pathway (Lee et al, 1995; Yeh et al, 1995; Egert et al, 1997). Moreover, we have shown that lactate also induces translocation of GLUT1 and GLUT4 to the plasma membrane, in the rat heart, through a PI3K independent pathway (Medina et al, 2002). This suggests that a common pathway based on metabolic stress is shared between hypoxia-, ischemia- and contraction-stimulated translocation of GLUT4. Since a common factor to all these conditions is the production and accumulation of lactate, these findings support our hypothesis that lactate may be involved in the cancer and metabolic stress-induced translocation of the glucose transporters (Medina et al, 2002).

A potential regulator of the pathway involved in metabolic stress-induced translocation of GLUT4 is AMP-activated protein kinase (AMPK) (Table5). Previous studies have shown that myocardial ischemia (Kudo, 1996) and skeletal muscle contraction (Winder and Hardie, 1996) activate AMPK and that activation of AMPK increases glucose uptake which is not inhibited by wortmannin. Finally, it has been shown that AMPK activation causes the translocation of myocardial GLUT4 and increases glucose uptake (Russell et al, 1999) (Table 5).

TABLE 5
Regulators and signaling pathways involved in glucose transport.


Regulator

Pathway GLUT Isoform Cell type Reference

Insulin

IR, PI3K GLUT4 Muscle, fat Czech&Corvera, 1999

IGF-I

IGF-IR, PI3K GLUT4 Muscle, fat Jullien et al, 1995
IGF-II IGF-IR, PI3K GLUT4 Muscle, fat Burguera et al, 1994

Contraction

AMPK GLUT4, GLUT1? Skeletal muscle Hayashi et al, 1998
Ischemia AMPK GLUT4 Heart muscle Russell et al, 1999
Hypoxia AMPK? GLUT4 Skeletal muscle Zierath, 1998

Nitric oxide

cGMP Presumed GLUT4 Skeletal muscle Young et al, 1997

Phorbol ester

PKC Presumed GLUT4 Skeletal muscle Hansen et al, 1997
a-Adrenergic agonists Gs protein GLUT4 Brown fat, muscle Shimizu et al, 1996
b-Adrenergic agonist Gi protein Presumed GLUT4 Heart muscle Fischer et al, 1996
Bradykinin Gq protein GLUT3 Skeletal muscle Kishi et al, 1998
Thrombin Gi protein GLUT3 Platelets Heijnen et al, 1997

Adenosine

Gq protein GLUT4 White and brown fat Smith et al, 1984

HORMONAL CONTROL OF GLUT EXPRESSION

Given the physiological importance of glucose uptake it is not surprising that GLUT expression is regulated, to some degree, by almost all of the know hormones. Insulin possesses long-term effects on GLUT content. Prolonged exposure to insulin, as occurs in type II diabetes, causes an increase in GLUT1 protein levels (Ciaraldi et al, 1995). This is the result of enhanced GLUT1 mRNA transcription (Garcia de Herreros & Birnbaum, 1989) and a rise in GLUT1 mRNA half-life (Maher & Harrison, 1990). Nuclear hormone receptor ligands such as testosterone, glucocorticoids, retinoic acid and thyroid hormones have been shown to alter GLUT expression (Rincon et al, 1996; Sakoda et al,2000; Rivenzon-Segal et al, 2001; Matosin-Matekalo et al,1999, respectively). Further reports have demonstrated that prolactin (Haney 2001), follicle stimulating hormone (FSH) (Kodaman and Behrman, 1999), noradrenaline and the antidiuretic hormone, vasopressin (Vannucci et al, 1994) can also mediate expression. Of particular interest to the authors is the role played by the female sex steroid hormones estrogen and progesterone in GLUT expression and the relation with endocrine cancers.

Sex Steroid Hormones

Sexual dimorphism exists in glucose metabolism. The role of sex hormones in this metabolism is apparent in the fetal rat where males demonstrate delayed lung maturation. This delay is speculated to be in part due to the predominantly female sex hormone estrogen causing an increase in GLUT1, and consequently an increase in glucose transport, in the female rat lung in comparison to the male (Hart et al, 1998). Additional work in the rat model has demonstrated that glucose uptake is impaired by the absence of estrogen or by the presence of progesterone. This suggests that estrogen increases metabolic activity and this process is finely regulated by the balance between estrogen and progesterone (Campbell and Febbraio 2001). In the aforementioned study, progesterone decreased GLUT4 in skeletal and adipose tissue, yet interestingly in another study of rat adipose tissue, physiological doses of estrogen or progesterone did not alter GLUT4 expression, while higher than physiological doses or the simultaneous co-addition of physiological doses of both hormones reduced GLUT4 (Sugaya et al, 2000; Sugaya et al, 1999). This indicates the complex interaction between signaling pathways can produce differing responses to steroid hormones in the same tissue or cell line. At any given time, the presence, absence or the activation level of stimuli, such as insulin-like growth factor (IGF) and insulin, is different. Thus the observed paradoxical results in response to sex steroid hormones may demonstrate that cross-talk with other growth factors can differentially regulate the GLUT family members.

In the Rhesus monkey brain, GLUT3 and GLUT4 expression is observed in the corticol neurones and GLUT1 in the capillaries and glial cells. Estrogen administration increased GLUT3 and GLUT4 expression and increased paranchymal if not vascular GLUT1 expression (Cheng et al, 2001). In this same study estrogen also increased the production of the IGF, suggesting that this growth factor plays a co-regulatory role in glucose uptake. In support of this argument, in mouse oocyte maturation the estrogen increase in GLUT1 expression was significantly lower in the absence of IGF (Zhou et al, 2000). The breast cancer drug Tamoxifen which possesses both estrogenic and anti-estrogen activities depending on both the target gene and tissue, also increased GLUT3 and GLUT4 in the Rhesus monkey brain, perhaps suggesting that the protective estrogenic effect in the brain is connected to GLUT regulation, and that Tamoxifen and other selective estrogen receptor modulators (SERMs) could confer some of these protective effects on the human brain (Cheng et al, 2001). In agreement with this hypothesis, estrogen was shown to increase GLUT1 and protect against brain capillary endothelial cell loss in reduced glucose conditions and anoxia (Shi et al, 1997) and reduce glucose transport inhibition in synaptosomes from the rat cerebral hemisphere (Keller et al, 1997).

To further dissect the mechanism of estrogen action Welch and Gorski (1999) demonstrated that in the rat uterus, estrogen increased glucose uptake in what appears to be both a transciptionally-independent and dependent mechanism. Estrogen causes an increase in glucose uptake in less than two hours and continues beyond eight hours. This early timeframe appears to suggest transcriptional independence, a theory that is confirmed by insensitivity to cyclohexamide and the observation that estrogen does not increase GLUT1 mRNA levels or GLUT1 and GLUT4 protein levels until after four hours of treatment. Presumably after eight hours, when levels of GLUT1 and GLU4 are elevated in response to estrogen, these proteins translocate to the membrane and augment glucose uptake. The possibility that at less than two hours estrogen induced glucose uptake was via translocation to the membrane was ruled out by the demonstration that both GLUT1 and GLUT4 localization was unchanged. This suggests that a GLUT1 and GLUT4-independent pathway is responsible for glucose uptake or that estrogen treatment causes a modification in the membrane localized GLUT proteins, thus facilitating glucose uptake. A conclusion from several publications is that hormone regulated glucose transport is not solely mediated by glucose transporters. In breast cancer biopsies no positive relationship was found between glucose uptake, determined by FDG, and expression of GLUTs (Avril et al, 2001). In comparison of two cell lines Aloj et al, (1999) reported that higher levels of glucose transporter protein do not guarantee increased glucose uptake. Marom et al, (2001) demonstrated that GLUT1 and GLUT3 transporter expression did not demonstrate a statistically significant correlation with FDG uptake in potentially resectable lung cancer. These results could be explained if it is the glucose phosphorylation, by hexokinase, and not the glucose transport which is the rate-limiting step in glucose uptake.

Collison et al, (2000) reported that in adipocytes estrogen treatment resulted in a reduction in the ability of insulin to stimulate glucose transport, demonstrating interaction between these two major signaling cascades, some of which have already been mentioned (Table 5). Previous work has demonstrated that estrogen and progesterone receptors can become transcriptionally active by the phosphorylation cascades set in motion by membrane receptors such as IGF and insulin (Klotz et al, 2002; Quesada and Etgen, 2001). Conversely, estrogen can impinge on the calcium, cAMP and phosphorylation pathways and thus mediate cell-specific responses (Flototto et al, 2001). To further elucidate these signaling pathway interactions cells are transfected with luciferase reporter constructs under the control of the GLUT promoters. In an example of this technique Montessuit &Thorburn (1999) demonstrated that 12-O-tetradecanoylphorbol-13-acetate (TPA) induced transcription from the GLUT1 promoter.

The breast and uterine endometrium are two of the classical target tissues for sex steroid hormone action. GLUT1, which is expressed in mammary tissue under normal conditions, is over-expressed in breast cancer tissue and has a high association with metastasis. As breast cancers are predominantly estrogen-driven, this suggests a correlation between GLUT expression and estrogen. Although aforementioned work in the rat and monkey has demonstrated such a relationship, Avril and colleagues (2001) reported that there was no correlation between estrogen receptor status and GLUT expression. The role of estrogen in GLUT over-expression remains elusive especially since it has been observed that in many advanced breast cancers estrogen receptor expression is lost. Both breast cancer biopsies and isolated cell lines have been shown to express GLUT5 (Zamora-Leon et al, 1996). GLUT5 is not expressed under normal conditions in the breast and is only expressed by a few tissues in the body, thus suggesting that breast cancers are utilizing fructose as an energy source in uncontrolled proliferation.

SUMMARY

Glucose is an important substrate for ATP production in all mammalian cells. However, because of its hydrophilic nature, it cannot enter the cell by simple diffusion.

For this it requires specific facilitative transport proteins which are subject to hormonal and environmental control.

The fact that glucose, and possibly fructose, is the only utilizable substrate available for energy production to ischemic cancers suggests that GLUTs have great therapeutic potential in combating this disease. This potential is not solely as prognostic markers, through their association with metastasis and thus poor patient prognosis, but also as direct targets of clinical intervention. Further therapeutic potential may be derived from a better understanding of the coordination between signaling pathways such as IGF, insulin and hormones, and with this knowledge the design of drugs to exploit this interaction for patient gain. To better understand this signaling pathway association, numerous cancer cell lines exist which express the GLUT1 through GLUT 5 family members (and potentially other members, Table 1). These cell lines (Table 4) will provide useful experimental models in which interactions can be dissected, prognostic markers characterized and potential drugs designed, before their transference to the clinic.

REFERENCES

AGUS DB, VERA JC, GOLDE DW (1999) Stromal cell oxidation: a mechanism by which tumors obtain vitamin C. Cancer Res 59: 4555-4558        [ Links ]

AGUS DB, GAMBHIR SS, PARDRIDGE WM, SPIELHOLZ C, BASELGA J, VERA JC, GOLDE DW (1997) Vitamin C crosses the blood-brain barrier in the oxidized form through the glucose transporters. J Clin Invest 100: 2842-8        [ Links ]

AHMED N, BERRIDGE MV (1999) N-glycosylation of glucose transporter-1 (Glut-1) is associated with increased transporter affinity for glucose in human leukemic cells. Leuk Res 23: 395-401         [ Links ]

AIRLEY R, LONCASTER J, DAVIDSON S, BROMLEY M, ROBERTS S, PATTERSON A, HUNTER R, STRATFORD I, WEST C (2001) Glucose transporter glut-1 expression correlates with tumor hypoxia and predicts metastasis-free survival in advanced carcinoma of the cervix. Clin Cancer Res 7: 928-934         [ Links ]

ALO PL, VISCA P, BOTTI C, GALATI GM, SEBASTIANI V, ANDREANO T, DI TONDO U, PIZER ES (2001) Immunohistochemical expression of human erythrocyte glucose transporter and fatty acid synthase in infiltrating breast carcinomas and adjacent typical/atypical hyperplastic or normal breast tissue. Am J Clin Pathol 116: 129-34         [ Links ]

ALOJ L, CARACO C, JAGODA E, ECKELMAN WC, NEUMANN RD (1999) Glut-1 and hexokinase expression: relationship with 2-fluoro-2-deoxy-d-glucose uptake in a431 and t47d cells in culture. Cancer Res 59(18): 4709-14         [ Links ]

ARA G, GRAVELIN LM, KADDURAH-DAOUK R, TEICHER BA (1998) Antitumor activity of creatine analogs produced by alterations in pancreatic hormones and glucose metabolism In Vivo 12: 223-31         [ Links ]

AVRIL N, MENZEL M, DOSE J, SCHELLING M, WEBER W, JANICKE F, NATHARATH W, SCHWAIGER M (2001) Glucose metabolism of breast cancer assessed by 18F-FDG PET: histologic and immunohistochemical tissue analysis. J Nucl Med 42: 9-16         [ Links ]

BAER SC, CASAUBON L, YOUNES M. (1997) Expression of the human erythrocyte glucose transporter GLUT1 in cutaneous neoplasia.J Am Acad Dermatol. 37: 575-577         [ Links ]

BARONI MG, CAVALLO MG, MARK M, MONETINI L, STOEHRER B, POZZILLI P (1999) Beta-cell gene expression and functional characterisation of the human insulinoma cell line CM. J Endocrinol 161: 59-68         [ Links ]

BERRIDGE MV, TAN AS, MCCOY KD, KANSARA M, RUDERT F (1996) CD95 (Fas/Apo-1)-induced apoptosis results in loss of glucose transporter function. J Immunol 156: 4092-9         [ Links ]

BINDER C, BINDER L, MARX D, SCHAUER A, HIDDEMANN W (1997) Deregulated simultaneous expression of multiple glucose transporter isoforms in malignant cells and tissues. Anticancer Res 17: 4299-4304         [ Links ]

BIRNBAUM MJ (1992) The insulin-sensitive glucose transporter. Int Rev Cytology 137A: 239-297         [ Links ]

BIRNBAUM MJ, HASPEL HC, ROSEN OM (1987) Transformation of rat fibroblasts by FSV rapidly increases glucose transporter gene. Science 235: 1495-1498         [ Links ]

BLAKEMORE SJ, ALEDO JC, JAMES J, CAMPBELL FC, LUCOCQ JM, HUNDAL HS (1995). The GLUT5 hexose transporter is also localized to the basolateral membrane of the human jejunum. Biochem J 309: 7-12         [ Links ]

BOADO RJ, BLACK KL, PARDRIDGE WM. (1994) Gene expression of GLUT3 and GLUT1 glucose transporters in human brain tumors. Brain Res Mol Brain Res 27: 51-57         [ Links ]

BODEN G, MURER E, MOZZOLI M (1994) Glucose transporter proteins in human insulinoma. Ann Intern Med 121: 109-12         [ Links ]

BROSIUS FC, LIU Y, NGUYEN N, SUN D, BARTLETT J, SCHWAIGER M (1997) Persistent myocardial ischemia increases GLUT1 transporter expression in both ischemic and non-ischemic heart regions. J Molec Cell Cardiol 29: 1675-1685         [ Links ]

BROT-LAROCHE E (1996) Differential regulation of the fructose transporters GLUT2 and GLUT5 in the intestinal cell line Caco-2. Proc Nutr Soc 55: 201-218         [ Links ]

BROWN RS, LEUNG JY, KISON PV, ZASADNY KR, FLINT A, WAHL RL (1999) Glucose transporters and FDG uptake in untreated primary human non-small cell lung cancer. J Nucl Med. 40: 556-65         [ Links ]

BROWN RS, WAHL RL (1993) Overexpression of Glut-1 glucose transporter in human breast cancer. An immunohistochemical study. Cancer 72: 2979-85         [ Links ]

BURGUERA BE, ELTON CW, CARO JF, TAPSCOTT EB, PORIES WJ, DIMARCHI R, SAKANO K, DOHM GL (1994) Stimulation of glucose uptake by insulin-like growth factor II in human muscle is not mediated by the insulin-like growth factor II/mannose 6-phosphate receptor. Biochem J 300: 781-785         [ Links ]

CHAN JY, KONG SK, CHOY YM, LEE CY, FUNG KP (1999) Inhibition of glucose transporter gene expression by antisense nucleic acids in HL-60 leukemia cells. Life Sci 65: 63-70         [ Links ]

CHANG S, LEE S, LEE C, KIM JI, KIM Y (2000) Expression of the human erythrocyte glucose transporter in transitional cell carcinoma of the bladder. Urology 55: 448-52         [ Links ]

CANTUARIA G, FAGOTTI A, FERRANDINA G, MAGALHAES A, NADJI M, ANGIOLI R, PENALVER M, MANCUSO S, SCAMBIA G (2001) GLUT-1 expression in ovarian carcinoma: association with survival and response to chemotherapy. Cancer 92: 1144-1150         [ Links ]

CANTUARIA G, MAGALHAES A, ANGIOLI R, MENDEZ L, MIRHASHEMI R, WANG J, WANG P, PENALVER M, AVERETTE H, BRAUNSCHWEIGER P (2000) Antitumor activity of a novel glyco-nitric oxide conjugate in ovarian carcinoma. Cancer 88: 381-388         [ Links ]

CHENG CM, COHEN M, WANG J, BONDY CA (2001) Estrogen augments glucose transporter and IGF1 expression in primate cerebral cortex. FASEB J 15: 907-915         [ Links ]

CIARALDI TP, ABRAMS L, NIKOULINA S, MUDALIAR S, HENRY RR. (1995) Glucose transport in cultured human skeletal muscle cells. Regulation by insulin and glucose in nondiabetic and non-insulin-dependent diabetes mellitus subjects. J Clin Invest 96: 2820-2827         [ Links ]

CLARSON LH, GLAZIER JD, SIDES MK, SIBLEY CP (1997) Expression of the facilitated glucose transporters (GLUT1 and GLUT3) by a choriocarcinoma cell line (JAr) and cytotrophoblast cells in culture. Placenta 18: 333-339         [ Links ]

CLAVO AC, BROWN RS, WAHL RL (1995) Fluorodeoxyglucose uptake in human cancer cell lines is increased by hypoxia. J Nucl Med. 36(9): 1625-1632         [ Links ]

CLOHERTY EK, DIAMOND DL, HEARD KS, CARRUTHERS A (1996) Regulation of GLUT1-mediated sugar transport by an antiport/uniport switch mechanism. Biochemistry 35: 13231-13239         [ Links ]

COLLISON M, CAMPBELL IW, SALT IP, DOMINICZAK AF, CONNELL JM, LYALL H, GOULD GW. (2000) Sex hormones induce insulin resistance in 3T3-L1 adipocytes by reducing cellular content of IRS proteins. Diabetologia. 43: 1374-1380.         [ Links ]

COLVILLE CA, SEATTER MJ, JESS TS, GOULD GW, THOMAS HM (1993) Kinetic analysis of liver-type (GLUT2) and brain-type (GLUT3) glucose transporter in Xenopus oocytes: substrate specificities and effects of transport inhibitors. Biochem J 290: 701-706         [ Links ]

CONCHA II, VELASQUEZ FV, MARTINEZ JM, ANGULO C, DROPPELMANN A, REYES AM, SLEBE JC, VERA JC, GOLDE DW (1997) Human erythrocytes express GLUT5 and transport fructose. Blood 89: 4190-4195         [ Links ]

CZECH MP, CORVERA S (1999) Signaling mechanisms that regulate glucose transport. J Biol Chem 274: 1865-1868         [ Links ]

DANG CV, SEMENZA GL (1999) Oncogenic alterations of metabolism. Trends Biochem Sci 24: 68-72         [ Links ]

DOEGE H, BOCIANSKI A, JOOST HG, SCHURMANN A (2000) Activity and genomic organization of human glucose transporter 9 (GLUT9), a novel member of the family of sugar transport facilitators predominantly expressed in brain and leukocytes. Biochem J 350: 771-776         [ Links ]

DOEGE H, SCHURMANN A, BAHRENBERG, BRAUERS A, JOOST HG (2000a) Glucose transporter 8 (GLUT8): a novel sugar facilitator with glucose transport activity. J Biol Chem 275: 16275-16280         [ Links ]

DOEGE H, BOCIANSKI A, SCHEEPERS A, AXER H, ECKEL J, JOOST HG, SCHURMANN A, (2001) Characterization of the human glucose transporter GLUT11, a novel sugat transport facilitator specifically expressed in heart muscle. Biochem J 359: 443-449         [ Links ]

DOENST T, TAEGTMEYER H (1998) Profound underestimation of glucose uptake by [18F]2-deoxy-2-fluoroglucose in reperfused rat heart muscle. Circulation 97: 2452-2462         [ Links ]

EGERT S, NGUYEN N, BROSIUS III FC, SCHWAIGER M (1997) Effects of wortmannin on insulin- and ischemia-induced stimulation of GLUT4 translocation and FDG uptake in perfused rat hearts. Cardiovas Res 35: 283-293         [ Links ]

EGERT S, NGUYEN N, SCHWAIGER M (1999) Contribution of _-adrenergic and _-adrenergic stimulation to ischemia induced glucose transport (GLUT) 4 and GLUT1 translocation in the isolated perfused rat heart. Circ Res 84: 1407-1415         [ Links ]

FISCHER Y, KAMP J, THOMAS J, POPPING S, ROSE H, CARPENE C, KAMMERMEIER H (1996) Signals mediating stimulation of cardiomyocyte glucose transport by the alpha-adrenergic agonist phenylephrine. Am J Physiol 270: C1211-C1220         [ Links ]

FLOTOTTO T, DJAHANSOUZI S, GLASER M, HANSTEIN B, NIEDERACHER D, BRUMM C, BECKMANN MW.Hormones and hormone antagonists: mechanisms of action in carcinogenesis of endometrial and breast cancer. Horm Metab Res 33: 451-457         [ Links ]

FUKUMOTO H, KAYANO T, BUSE JB, EDWARDS Y, PILCH PF, BELL GI, SEINO S (1989) Cloning and characterization of the major insulin-responsive glucose transporter expressed in human skeletal muscle and other insulin-responsive tissues. J Biol Chem 264: 7776-7779         [ Links ]

FULLER W EATON P, MEDINA RA, BELL J, SHATTOCK MJ (2001) Differential centrifugation separates sarcolemmal and endosomal membranes from Langendorff-perfused rat hearts. Analytical Biochem 293: 216-223         [ Links ]

FURUDOI A, TANAKA S, HARUMA K, YOSHIHARA M, SUMII K, KAJIYAMA G, SHIMAMOTO F (2001) Clinical significance of human erythrocyte glucose transporter 1 expression at the deepest invasive site of advanced colorectal carcinoma. Oncology 60: 162-169         [ Links ]

GARCIA DE HERREROS A, BIRNBAUM MJ. (1989) The regulation by insulin of glucose transporter gene expression in 3T3 adipocytes. J Biol Chem 264: 9885-9890         [ Links ]

GARVEY WT, HARDIN D, JUHASZOVA M, DOMINGUEZ JH (1993) Effect of diabetes on myocardial glucose transport system in rats. Implications for diabetic cardiomyopathy. Am J Physiol 264: H837-H844         [ Links ]

GERMAN MS (1993) Glucose sensing in pancreatic islet beta cells: the key role of glucokinase and the glycolytic intermediates. Proc Natl Acad Sci USA 90: 1781-1785         [ Links ]

GLICK RP, UNTERMAN TG, LACSON R (1993) Identification of insulin-like growth factor (IGF) and glucose transporter-1 and -3 mRNA in CNS tumors. Regul Pept 48: 251-256         [ Links ]

GOULD GW, THOMAS HM, JESS TJ, BELL GI (1991) Expression of human glucose transporters in Xenopus oocytes: kinetic characterization and substrate specificities of the erythrocyte, liver and brain isoforms. Biochemistry 30: 5139-5145         [ Links ]

GROVER-MCKAY M, WALSH SA, SEFTOR EA, THOMAS PA, HENDRIX MJ (1998) Role for glucose transporter 1 protein in human breast cancer. Pathol Oncol Res 4: 115-120         [ Links ]

HANEY PM (2001) Localization of the GLUT1 glucose transporter to brefeldin A-sensitive vesicles of differentiated CIT3 mouse mammary epithelial cells. Cell Biol Int 25: 277-288         [ Links ]

HANSEN PA, CORBETT JA, HOLLOSZY JO (1997) Phorbol esters stimulate muscle glucose transport by a mechanism distinct from the insulin and hypoxia pathways. Am J Physiol 273: E28-E36         [ Links ]

HABER RS, RATHAN A, WEISER KR, PRITSKER A, ITZKOWITZ SH, BODIAN C, SLATER G, WEISS A, BURSTEIN DE (1998) GLUT1 glucose transporter expression in colorectal carcinoma: a marker for poor prognosis. Cancer 83: 34-40         [ Links ]

HABER RS, WEISER KR, PRITSKER A, REDER I, BURSTEIN DE (1997) GLUT1 glucose transporter expression in benign and malignant thyroid nodules. Thyroid 7: 363-7

HAHN T, BARTH S, HOFMANN W, REICH O, LANG I, DESOYE G (1998) Hyperglycemia regulates the glucose-transport system of clonal choriocarcinoma cells in vitro. A potential molecular mechanism contributing to the adjunct effect of glucose in tumor therapy. Int J Cancer. 78: 353-60         [ Links ]

HARRIS DS, SLOT JW, GEUZE HJ, JAMES DE (1992) Polarized distribution of glucose transporter isoforms in Caco-2 cells. Proc Natl Acad Sci USA 89: 7556-7560         [ Links ]

HART CD, FLOZAK AS, SIMMONS RA (1998) Modulation of glucose transport in fetal rat lung: a sexual dimorphism. Am J Respir Cell Mol Biol 19: 63-70         [ Links ]

HAYASHI T, HIRSHMAN MF, KURTH EJ, WINDER WW, GOODYEAR LJ (1997) Evidence for 5' AMP-activated protein kinase mediation of the effect of muscle contraction on glucose transport. Diabetes 47: 1369-73         [ Links ]

HEIJNEN HF, OORSCHOT V, SIXMA JJ, SLOT JW, JAMES DE (1997) Thrombin stimulates glucose transport in human platelets via the translocation of the glucose transporter GLUT-3 from alpha-granules to the cell surface. J Cell Biol 138: 323-330         [ Links ]

HEIMBERG H, DE VOS A, VANDERCAMMEN A, VAN SCHAFTINGEN E, PIPELEERS D, SCHUIT F (1993) Heterogeneity in glucose sensitivity among pancreatic beta-cells is correlated to differences in glucose phosphorylation rather than glucose transport. EMBO J 12: 2873-2879         [ Links ]

HIGASHI K, UEDA Y, SAKURAI A, WANG XM, XU L, MURAKAMI M, SEKI H, OGUCHI M, TAKI S, NAMBU Y, TONAMI H, KATSUDA S, YAMAMOTO I (2000) Correlation of Glut-1 glucose transporter expression. Eur J Nucl Med. 27: 1778-85         [ Links ]

HUGHES SD, JOHNSON JH, QUAADE C, NEWGARD CB (1992) Engineering of glucose-stimulated insulin secretion and biosynthesis in non-islet cells. Proc Natl Acad Sci USA 89: 688-692         [ Links ]

ILIOPOULOS O, LEVY AP, JIANG C, KAELIN WG JR, GOLDBERG MA (1996) Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. Proc Natl Acad Sci U S A. 93: 10595-10599         [ Links ]

ISMAIL-BEIGI F (1993) Metabolic regulation of glucose transport. J Membr Biol 135: 1-10         [ Links ]

ITO S, NEMOTO T, SATOH S, SEKIHARA H, SEYAMA Y, KUBOTA S (2000) Human rhabdomyosarcoma cells retain insulin-regulated glucose transport activity through glucose transporter 1. Arch Biochem Biophys 373: 72-82         [ Links ]

ITO T, NOGUCHI Y, SATOH S, HAYASHI H, INAYAMA Y, KITAMURA H (1998) Expression of facilitative glucose transporter isoforms in lung carcinomas: its relation to histologic type, differentiation grade, and tumor stage. Mod Pathol 11: 437-443         [ Links ]

JAMES DE, KRAEGEN EW, CHISHOLM DJ (1985) Muscle glucose metabolism in exercising rats: comparison with insulin stimulation. Am J Physiol 248: E575-E580         [ Links ]

JAMES DE, PIPER RC (1994) Insulin resistance, diabetes, and the insulin-regulated trafficking of GLUT4. J Cell Biol 126: 1123-1126         [ Links ]

JAMES DE, PIPER RC, SLOT JW (1994) Insulin stimulation of GLUT4 translocation: a model for regulated recycling. Trends Cell Biol 4: 120-126         [ Links ]

JHUN BH, RAMPAL AL, LIU HZ, LACHAAL M, JUNG CY (1992) Effects of insulin on steady state kinetics of GLUT4 subcellular distribution in rat adipocytes: evidence of constitutive GLUT4 recycling. J Biol Chem 267: 17710-17715         [ Links ]

JOOST HG, THORENS B (2001) The extended GLUT-family of sugar/polyol transport facilitators- nomenclature, sequence characteristics, and potential function of its novel members. Mol Memb Biol 18: 247-256         [ Links ]

JUNG CY (1998) Proteins that interact with facilitative glucose transporters: implications for function. Exp Physiol 83: 267-273         [ Links ]

JULLIEN D, HEYDRICK S, GAUTIER N, VAN OBBERGHENE (1995) Effects of insulin and insulin-like growth factor-I on glucose transport and its transporters in soleus muscle of lean and obese mice. Metabolism 44: 18-23         [ Links ]

KANZAKI M, WATSON RT, ARTEMYEV NO, PESSIN JE (2000) The trimeric GTP-binding protein (G(q)/G(11)) alpha subunit is required for insulin-stimulated GLUT4 translocation in 3T3L1 adipocytes. J Biol Chem 275: 7167-7175         [ Links ]

KASHIWAYA Y, SATO K, TSUCHIYA N, THOMAS S, FELL DE, VEECH RL, PASSONNEAU JV (1994) Control of glucose utilization in working perfused rat heart. J Biol Chem 269: 25502-25514         [ Links ]

KATZ EB, STENBIT AE, HATTON K, DEPINHO R, CHARRON MJ (1995) Cardiac and adipose tissue abnormalities but not diabetes in mice deficient in GLUT4. Nature 377: 151-155         [ Links ]

KAWAMURA T, KUSKABE T, SUGINO T, WATANABE K, FUKUDA T, NASHIMOTO A, HONMA K, SUZUKI T (2001) Expression of glucose transporter-1 in human gastric carcinoma: association with tumor aggressiveness, metastasis, and patient survival. Cancer 92:634-641         [ Links ]

KAYANO T, FUKUMOTO H, EDDY RL, FAN YS, BYERS MG, SHOWS TB, BELL GI (1988) Evidence for a family of human glucose transporter-like proteins. Sequence and gene localization of a protein expressed in fetal skeletal muscle and other tissues. J Biol Chem 263: 15245-15248         [ Links ]

KAYANO T, BURANT CF, FUKUMOTO H, GOULD GW, FAN Y, EDDY RL, BYERS MG, SEINO S, BELL GI (1990) Human facilitative glucose transporters. Isolation, functional characterization, and gene localization of cDNAs encoding an isoform (GLUT5) expressed in small intestine, kidney, muscle, and adipose tissue and an unusual glucose transporter pseudogene-like sequence (GLUT6). J Biol Chem 265: 13267-13282         [ Links ]

KELLER K, STRUBE M, MUECKLER M (1989) Functional expression of the human HepG2 and rat adipocytes glucose transporters in Xenopus oocytes. J Biol Chem 264: 18884-18889         [ Links ]

KELLER JN, GERMEYER A, BEGLEY JG, MATTSON MP (1997) 17Beta-estradiol attenuates oxidative impairment of synaptic Na+/K+-ATPase activity, glucose transport, and glutamate transport induced by amyloid beta-peptide and iron. J Neurosci Res 50(4):522-30         [ Links ]

KISHI K, MUROMOTO N, KAKAYA Y, MIYATA I, HAGI A, HAYASHI H, EBINA Y (1998) Bradykinin directly triggers GLUT4 translocation via an insulin-independent pathway. Diabetes 47: 550-558         [ Links ]

KITAGAWA T, TSURUHARA Y, HAYASHI M, ENDO T, STANBRIDGE EJ (1995) A tumor-associated glycosylation change in the glucose transporter GLUT1 controlled by tumor suppressor function in human cell hybrids. J Cell Sci 108 ( Pt 12):3735-43         [ Links ]

KLOTZ DM, CURTIS HEWITT S, CIANA P, RAVISCIONI M, LINDZEY JK, FOLEY J, MAGGI A, DIAUGUSTINE RP, KORACH KS (2002) Requirement of estrogen receptor-{alpha} in insulin-like growth factor-1-induced uterine responses and in vivo evidence for insulin-like growth factor-1/estrogen receptor cross-talk. J Biol Chem (in press)         [ Links ]

KNAACK D, FIORE DM, SURANA M, LEISER M, LAURANCE M, FUSCO-DEMANE D, HEGRE OD, FLEISCHER N, EFRAT S (1994) Clonal insulinoma cell line that stably maintains correct glucose responsiveness. Diabetes 43(12):1413-7         [ Links ]

KODAMAN PH, BEHRMAN HR (1999) Hormone-regulated and glucose-sensitive transport of dehydroascorbic acid in immature rat granulosa cells. Endocrinology 140(8):3659-65         [ Links ]

KRAEGEN EW, SOWDEN JA, HALSTEAD MB, CLARK PW, RODNICK KJ, CHISHOLM DJ, JAMES DE (1993) Glucose transporters and in-vivo glucose uptake in skeletal and cardiac muscle: fasting, insulin stimulation and immunoisolation studies of GLUT1 and GLUT4. Biochem J 295: 287-293         [ Links ]

KUDO N, GILLESPIE JG, KUNG L, WITTERS LA, SCHULZ R, CLANACHAN AS, LOPASCHUCK GD (1996) Characterization of 5'AMP-activated protein kinase activity in the heart and its role in inhibiting acetyl-CoA carboxylase during reperfusion following ischemia. Biochim Biophys Acta 1301: 67-75         [ Links ]

KUMAGAI AK, DWYER KJ, PARDRIDGE WM (1994) Differential glycosylation of the GLUT1 glucose transporter in brain capillaries and choroids plexus. Biochim Biophys Acta 1193: 24-30         [ Links ]

KURATA T, OGURI T, ISOBE T, ISHIOKA S, YAMAKIDO M (1999) Differential expression of facilitative glucose transporter (GLUT) genes in primary lung cancers and their liver metastases. Jpn J Cancer Res 90(11):1238-43         [ Links ]

KUROSAKI M, HORI T, TAKATA K, KAWAKAMI H, HIRANO H (1995) Immunohistochemical localization of the glucose transporter GLUT1 in choroid plexus papillomas. Noshuyo Byori. 12(1):69-73         [ Links ]

LACHAAL M, RAMPAL AL, LEE W, JUNG CY (1996) Transmembrane glucose channel: affinity labeling with a transportable D-glucose diazirine. J Biol Chem 271: 5225-5230         [ Links ]

LAZAR V, BIDART JM, CAILLOU B, MAHE C, LACROIX L, FILETTI S, SCHLUMBERGER M (1999) Expression of the Na+/I- symporter gene in human thyroid tumors: a comparison study with other thyroid-specific genes. J Clin Endocrinol Metab. 84(9):3228-34.         [ Links ]

LEE AD, HANSEN PA, HOLLOSZY JO (1995) Wortmannin inhibits insulin-stimulated but not contraction-stimulated glucose transport activity in skeletal muscle. FEBS Lett 361: 51-54         [ Links ]

LODA M, XU X, PESSION A, VORTMEYER A, GIANGASPERO F (2000) Membranous expression of glucose transporter-1 protein (GLUT-1) in embryonal neoplasms of the central nervous system. Neuropathol Appl Neurobiol 26(1):91-7         [ Links ]

MCMAHON RJ, HWANG JB, FROST SC (2000) Glucose deprivation does not affect GLUT1 targeting in 3T3-L1 adipocytes. Biochem Biophys Res Comm 273: 859-64         [ Links ]

MCVIE-WYLIE AJ, LAMSON DR, CHEN YT (2001) Molecular cloning of a novel member of the GLUT family of transporters, SLC2A10 (GLUT10), localized on chromosome 20q13.1: a candidate gene for NIDDM susceptibility. Genomics 72:113-117         [ Links ]

MAGNUSON MA, ANDREONE TL, PRINTZ RL, KOCH S, GRANNER DK (1989) Rat glucokinase gene: structure and regulation of insulin. Proc Natl Acad Sci USA 86: 4838.4842         [ Links ]

MAHER F, VANNUCCI SJ, SIMPSON IA (1993) Glucose transporter isoforms in brain: absence of GLUT3 from the blood-brain-barrier. J Cereb Blood Flow Metabol 12: 342-345         [ Links ]

MAHER F, VANNUCCI SJ, SIMPSON IA (1994) Glucose transporter proteins in brain. FASEB J 8: 1003-1011         [ Links ]

MAHRAOUI L, RODOLOSSE A, BARBAT A, DUSSAULX E, ZWEIBAUM A, ROUSSET M, BROT-LAROCHE E (1994) Presence and differential expression of SGLT1, GLUT1, GLUT2, GLUT3 and GLUT5 hexose-transporter mRNAs in Caco-2 cell clones in relation to cell growth and glucose consumption. Biochem J 298 Pt 3:629-33.         [ Links ]

MANCHESTER J, KONG X, NERBORNE J, LOWRY OH, LAWRENCE JC (1994) Glucose transport and phosphorylation in single cardiac myocyte: rate-limiting steps in glucose metabolism. Am J Physiol 266: E326-E333         [ Links ]

MAROM EM, ALOIA TA, MOORE MB, HARA M, HERNDON JE 2ND, HARPOLE DH JR, GOODMAN PC, PATZ EF JR. (2001) Correlation of FDG-PET imaging with Glut-1 and Glut-3 expression in early-stage non-small cell lung cancer. Lung Cancer 33(2-3):99-107         [ Links ]

MATOSIN-MATEKALO M, MESONERO JE, LAROCHE TJ, LACASA M, BROT-LAROCHE E. (1999) Glucose and thyroid hormone co-regulate the expression of the intestinal fructose transporter GLUT5. Biochem J 339 ( Pt 2):233-9         [ Links ]

MEDINA RA, SOUTHWORTH R, FULLER W, GARLICK PB (2002) Lactate-induced translocation of GLUT1 and GLUT4 is not mediated by phosphatidylinositol-3-kinase pathway in the rat heart. Basic Res Cardiol 97: 168-176         [ Links ]

MELLANEN P, MINN H, GRENMAN R, HARKONEN P (1994) Expression of glucose transporters in head-and-neck tumors. Int J Cancer 56: 622-9         [ Links ]

MESONERO J, MATOSIN M, CAMBIER D, RODRIGUEZ-YOLDI MJ, BROT-LAROCHE E (1995) Sugar-dependent expression of the fructose transporter GLUT5 in Caco-2 cells. Biochem J 312:757-62         [ Links ]

MONTESSUIT C, PAPAGEORGIU I, REMONDINO-MULLER A, TARDY I, LERCH R (1998) Post-ischemic stimulation of 2-deoxyglucose uptake in rat myocardium: role of translocation of GLUT4. J Molec Cell Cardiol 30: 393-403         [ Links ]

MONTESSUIT C, THORBURN A. (1999) Transcriptional activation of the glucose transporter GLUT1 in ventricular cardiac myocytes by hypertrophic agonists. J Biol Chem 274(13):9006-12         [ Links ]

MORIYAMA N, KURIMOTO S, KAWABE K, TAKATA K, HIRANO H (1997) Immunohistochemical expression of glucose transporter-1 in human penile proliferative lesions. Histochem J. 29: 273-8.         [ Links ]

MUECKLER M, CARUSO C, BALDWIN SA, PANICO M, BLENCH I, MORRIS HR, ALLARD WJ, LIENHARD GE, LODISH HF (1985) Sequence and structure of human glucose transporter. Science 229: 941-945         [ Links ]

MUECKLER M (1994) Facilitative glucose transporters. Eur J Biochem 219: 713-725         [ Links ]

NAGAMATSU S, KORNHAUSER JM, BURANT CF, SEINO S, MAYO KE, BELL GI (1992) Glucose transporter expression in brain. cDNA sequence of mouse GLUT3, the brain facilitative glucose transporter isoform, and identification of sites of expression by in-situ hybridization. J Biol Chem 267: 467-472         [ Links ]

NAGAMATSU S, SAWA H, INOUE N, NAKAMICHI Y, TAKESHIMA H, HOSHINO T (1994) Gene expression of GLUT3 glucose transporter regulated by glucose in vivo in mouse brain and in vitro in neuronal cell cultures from rat embryos. Biochem J 300: 125-131         [ Links ]

NAGAMATSU S, SAWA H, WAKIZAKA A, HOSHINO T (1993) Expression of facilitative glucose transporter isoforms in human brain tumors. J Neurochem 61: 2048-53.         [ Links ]

NAGAMATSU S, SAWA H, NAKAMICHI Y, KATAHIRA H, INOUE N (1994a) Developmental expression of GLUT3 glucose transporter in rat brain. FEBS Lett 346: 161-164         [ Links ]

NGUYEN VTB, MOSSBERG KA, TEWSON TJ, WONG WH, ROWE RW, COLEMAN GA, TAEGTMEYER H (1990) Temporal analysis of myocardial glucose metabolism by 2-[18F]fluoro-2-deoxy-D-glucose. Am J Physiol 259: H1022-H1031         [ Links ]

NISHIMURA H, PALLARDO FV, SEINER GA, VANNUCCI S, SIMPSON IA, BIRNBAUM MJ (1993) Kinetics of GLUT1 and GLUT4 glucose transporters expressed in Xenopus oocytes. J Biol Chem 268: 8514- 8520         [ Links ]

NOGUCHI Y, MARAT D, SAITO A, YOSHIKAWA T, DOI C, FUKUZAWA K, TSUBURAYA A, SATOH S, ITO T (1999) Expression of facilitative glucose transporters in gastric tumors. Hepatogastroenterology. 46: 2683-9         [ Links ]

NORTH PE, WANER M, JAMES CA, MIZERACKI A, FRIEDEN IJ, MIHM MC JR (2001) Congenital nonprogressive hemangioma: a distinct clinicopathologic entity unlike infantile hemangioma. Arch Dermatol 137: 1607-20         [ Links ]

OGAWA J, INOUE H, KOIDE S (1997) Glucose-transporter-type-I-gene amplification correlates with sialyl-Lewis-X synthesis and proliferation in lung cancer. Int J Cancer 74: 189-92         [ Links ]

OGURA K, SAKATA M, OKAMOTO Y, YASUI Y, TADOKORO C, YOSHIMOTO Y, YAMAGUCHI M, KURACHI H, MAEDA T, MURATA Y (2000) 8-bromo-cyclicAMP stimulates glucose transporter-1 expression in a human choriocarcinoma cell line. J Endocrinol. 164: 171-8         [ Links ]

OLSON AL, PESSIN JE (1996) Structure, function, and regulation of the facilitative glucose transporter gene family. Annu Rev Nutr 16: 235-256         [ Links ]

ONETTI R, BAULIDA J, BASSOLS A (1997) Increased glucose transport in ras-transformed fibroblasts: a possible role for N-glycosylation of GLUT1. FEBS Letters. 407: 267-70         [ Links ]

PAPADOPOULOS KP, COLOVAI AI, MAFFEI A, JARAQUEMADA D, SUCIU-FOCA N, HARRIS PE (1996) Tissue-specific self-peptides bound by major histocompatibility complex class I molecules of a human pancreatic beta-cell line. Diabetes 45: 1761-5         [ Links ]

PARDRIDGE WM, BOADO RJ, FARREL CR (1990) Brain-type glucose transporter (GLUT-1) is selectively localizes to the blood-brain-barrier. Studies with quantitative Western blotting and in-situ hybridization. J Biol Chem 265: 18035-18040         [ Links ]

PEDERSEN PL (1978) Tumor mitochondria and the bioenergetics of cancer cells. Prog Exp Tumor Res 22: 190-274         [ Links ]

PHAY JE, HUSSAIN HB, MOLEY JF (2000) Cloning and expression analysis of a novel member of the facilitative glucose transporter family, SLC2A9 (GLUT9). Genomics 66: 217-220         [ Links ]

QUESADA A, ETGEN AM. (2001) Insulin-like growth factor-1 regulation of alpha(1)-adrenergic receptor signaling is estradiol dependent in the preoptic area and hypothalamus of female rats. Endocrinology 142: 599-607         [ Links ]

RAO UN, FINKELSTEIN SD, JONES MW (1999) Comparative immunohistochemical and molecular analysis of uterine and extrauterine leiomyosarcomas. Mod Pathol. 12: 1001-9         [ Links ]

REISSER C, EICHHORN K, HEROLD-MENDE C, BORN AI, BANNASCH P (1999) Expression of facilitative glucose transport proteins during development of squamous cell carcinomas of the head and neck. Int J Cancer. 80: 194-8         [ Links ]

RESKE SN, GRILLENBERGER KG, GLATTING G, PORT M, HILDEBRANDT M, GANSAUGE F, BEGER HG (1997) Overexpression of glucose transporter 1 and increased FDG uptake in pancreatic carcinoma. J Nucl Med 38: 1344-8         [ Links ]

RINCON J, HOLMANG A, WAHLSTROM EO, LONNROTH P, BJORNTORP P, ZIERATH JR, WALLBERG-HENRIKSSON H. (1996) Mechanisms behind insulin resistance in rat skeletal muscle after oophorectomy and additional testosterone treatment. Diabetes 45: 615-21.         [ Links ]

RIVAS CI, VERA JC, GUAIQUIL VH, VELASQUEZ FE, BORQUEZ-OJEDA OA, CARCOMA JC, CONCHA II, GOLDE DW (1997) Increased uptake and accumulation of vitamin C in immunodeficiency virus 1-infected hematopoetic cell lines. J Biol Chem 272: 5814-5820         [ Links ]

RIVENZON-SEGAL D, RUSHKIN E, POLAK-CHARCON S, DEGANI H (2000) Glucose transporters and transport kinetics in retinoic acid-differentiated T47D human breast cancer cells. Am J Physiol Endocrinol Metab 279: E508-519         [ Links ]

ROGERS S, JAMES DE, BEST JD (1998) Identification of novel facilitative transporter like protein-GLUT8. Diabetes 47: A45         [ Links ]

RUSSELL RR, BERGERON R, SHULMAN GI, YOUNG LH (1999) Translocation of myocardial GLUT4 and increased glucose uptake through activation of AMPK by AICAR. Am J Physiol 277: H643-H649         [ Links ]

SAKASHITA M, AOYAMA N, MINAMI R, MAEKAWA S, KURODA K, SHIRASAKA D, ICHIHARA T, KURODA Y, MAEDA S, KASUGA M (2001) Glut1 expression in T1 and T2 stage colorectal carcinomas: its relationship to clinicopathological features. Eur J Cancer. 37: 204-9         [ Links ]

SAKODA H, OGIHARA T, ANAI M, FUNAKI M, INUKAI K, KATAGIRI H, FUKUSHIMA Y, ONISHI Y, ONO H, FUJISHIRO M, KIKUCHI M, OKA Y, ASANO T (2000) Dexamethasone-induced insulin resistance in 3T3-L1 adipocytes is due to inhibition of glucose transport rather than insulin signal transduction. Diabetes 49: 1700-8         [ Links ]

SEINO Y, YAMAMOTO T, INOUE K, IMAMURA M, KADOWAKI S, KOJIMA H, FUJIKAWA J, IMURA H (1993) Abnormal facilitative glucose transporter gene expression in human islet cell tumors. J Clin Endocrinol Metab 76: 75-8         [ Links ]

SHAH SW, ZHAO H, LOW SY, MCARDLE HJ, HUNDAL HS (1999) Characterization of glucose transport and glucose transporters in the human choriocarcinoma cell line, BeWo. Placenta. 20: 651-619         [ Links ]

SHI J, ZHANG YQ, SIMPKINS JW (1997) Effects of 17beta-estradiol on glucose transporter 1 expression and endothelial cell survival following focal ischemia in the rats. Exp Brain Res 117: 200-206         [ Links ]

SHIMIZU Y, KIELAR D, MINOKOSHI Y, SHIMAZU T (1996) Noradrenaline increases glucose transport into brown adipocytes in culture by a mechanism different from that of insulin. Biochem J 314: 485-490         [ Links ]

SLOT JW, GEUZE HJ, GIGENBACK S, JAMES DE, LIENHARD GE (1991) Translocation of the glucose transporter GLUT4 in cardiac myocytes of the rat. Proc Natl Acad Sci USA 88: 7815-7819         [ Links ]

SMITH U, KURODA M, SIMPSON LA (1984) Counter-regulation of insulin-stimulated glucose transport by catecholamines in the isolated rat adipose cell. J Biol Chem 259: 8758-8763         [ Links ]

STEPHENS JM, PILCH PF (1995) The metabolic regulation and vesicular transport of GLUT4, the major insulin-responsive glucose transporter. Endocrine Rev 16: 529-546.         [ Links ]

SUGAYA A, SUGIYAMA T, YANASE S, SHEN XX, MINOURA H, TOYODA N. (2000) Expression of glucose transporter 4 mRNA in adipose tissue and skeletal muscle of ovariectomized rats treated with sex steroid hormones. Life Sci. 66: 641-648         [ Links ]

SUGAYA A, SUGIYAMA T, YANASE S, TERADA Y, TOYODA N. (1999) Glucose transporter 4 (GLUT4) mRNA abundance in the adipose tissue and skeletal-muscle tissue of ovariectomized rats treated with 17 beta-estradiol or progesterone. J Obstet Gynaecol Res. 25: 9-14         [ Links ]

SUZUKI K, KONOT (1980). Evidence that insulin causes translocation of glucose transport activity to the plasma membrane from an intracellular storage site. Proc Natl Acad Sci USA 77: 2542-2545.         [ Links ]

THORENS B, CHENG Z-Q, BROWN D, LODISH H (1990) Liver glucose transporter: a basolateral protein in hepatocytes and intestine and kidney cells. Am J Physiol 259: C279-C285         [ Links ]

TSUKAMOTO H, MISHIMA H, HIRATA K, SATO E, KUROKAWA T, ISHIBASHI S (1997) Differences in the expression of glucose transporter protein isoforms in human retinoblastoma cell lines. Jpn J Ophthalmol 41: 226-230         [ Links ]

VANNUCCI SJ, MAHER F, KOEHLER E, SIMPSON IA (1994) Altered expression of GLUT-1 and GLUT-3 glucose transporters in neurohypophysis of water-deprived or diabetic rats. Am J Physiol 267: E605-611         [ Links ]

VERA JC, RIVAS CI, ZHANG RH, FARBER CN, GOLDE DW (1994) Human HL-60 myeloid leukemia cells transport dehydoascorbic acid via the glucose transporters and accumulate reduced ascorbic acid. Blood 84: 1628-1634         [ Links ]

WAKI A, KATO H, YANO R, SADATO N, YOKOYAMA A, ISHII Y, YONEKURA Y, FUJIBAYASHI Y. (1998) The importance of glucose transport activity as the rate-limiting step of 2-deoxyglucose uptake in tumorcells in vitro. Nucl Med Biol. 25: 593-597         [ Links ]

WANG BY, KALIR T, SABO E, SHERMAN DE, COHEN C, BURSTEIN DE (2000) Immunohistochemical staining of GLUT1 in benign, hyperplastic, and malignant endometrial epithelia. Cancer 88: 2774-2781         [ Links ]

WARBURG OH (1956) Science 123: 309-314         [ Links ]

WATANABE T, NAGAMATSU S, MATSUSHIMA S, KONDO K, MOTOBU H, HIROSAWA K, MABUCHI K, KIRINO T, UCHIMURA H (1999) Developmental expression of GLUT2 in the rat retina. Cell Tissue Res. 298: 217-223         [ Links ]

WELCH RD, GORSKI J. (1999) Regulation of glucose transporters by estradiol in the immature rat uterus. Endocrinology. 140: 3602-3608         [ Links ]

WINDER WW, HARDIE DG (1996) Inactivation of acetyl-CoA carboxylase and activation of AMP-activated protein kinase in muscle during exercise. Am J Physiol 270: E299-E304         [ Links ]

YEH JI, GULVE EA, RAMEH L, BIRNBAUM MJ (1995) The effects of wortmannin on rat skeletal muscle: dissociation of signaling pathways for insulin- and contraction- activated hexose transport. J Biol Chem 270: 2107-2111         [ Links ]

YOUNES M, BROWN RW, MODY DR, FERNANDEZ L, LAUCIRICA R. (1995) GLUT1 expression in human breast carcinoma: correlation with known prognostic markers. Anticancer Res. 15: 2895-2898         [ Links ]

YOUNES M, BROWN RW, STEPHENSON M, GONDO M, CAGLE PT. (1997a) Overexpression of GLUT1 and GLUT3 in stage I nonsmall cell lung carcinoma is associated with poor survival. Cancer 80:1046-51.         [ Links ]

YOUNES M, JUAREZ D, LECHAGO LV, LERNER SP. (2001) GLUT 1 expression in transitional cell carcinoma of the urinary bladder is associated with poor patient survival. Anticancer Res 2001 (1B): 575-578         [ Links ]

YOUNES M, LECHAGO LV, SOMOANO JR, MOSHARAF M, LECHAGO J. (1997b) Immunohistochemical detection of GLUT3 in human tumors and normal tissues. Anticancer Res. 17(4A): 2747-2750         [ Links ]

YOUNES M, LECHAGO J, CHAKRABORTY S, OSTROWSKI M, BRIDGES M, MERIANO F, SOLCHER D, BARROSO A, WHITMAN D, SCHWARTZ J, JOHNSON C, SCHMULEN AC, VERM R, BALSAVER A, CARLSON N, ERTANT A. (2000a) Relationship between dysplasia, p53 protein accumulation, DNA ploidy, and GLUT1 overexpression in Barrett metaplasia. Scand J Gastroenterol. 35(2): 131-137         [ Links ]

YOUNES M, PATHAK M, FINNIE D, SIFERS RN, LIU Y, SCHWARTZ MR. (2000b) Expression of the neutral amino acids transporter ASCT1 in esophageal carcinomas.Anticancer Res 5C: 3775-3779         [ Links ]

YOUNES M, LECHAGO LV, LECHAGO J.(1996) Overexpression of the human erythrocyte glucose transporter occurs as a late event in human colorectal carcinogenesis and is associated with an increased incidence of lymph node metastases. Clin Cancer Res 2(7): 1151-1154         [ Links ]

YOUNG ME, RADDA GK, LEIGHTON B (1997) Nitric oxide stimulates glucose transport and metabolism in rat skeletal muscle in vitro. Biochem J 322: 223-228         [ Links ]

ZAMORA-LEON SP, GOLDE DW, CONCHA II, RIVAS CI, DELGADO-LOPEZ F, BASELGA J, NUALART F, VERA JC. (1996) Expression of the fructose transporter GLUT5 in human breast cancer. Proc Natl Acad Sci USA 93(5): 1847-1852         [ Links ]

ZENG H, PARTHASARATHY R, RAMPAL AL, JUNG CY (1996) Proposed structure of putative glucose channel in GLUT1 facilitative glucose transporter. Biophys J 1996 70: 14-21         [ Links ]

ZHANG M, OLSSON Y (1996) Vascular expression of glucose transporter in and around hematogenous metastases of the human brain. Immunohistochemical observations. APMIS. 104: 293-301         [ Links ]

ZHOU J, BIEVRE M, BONDY CA (2000) Reduced GLUT1 expression in Igf1-/- null oocytes and follicles. Growth Horm IGF Res 10: 111-117         [ Links ]

ZIERATH RA, TSAO T-S, STENBIT AE, RYDER JW, GALUSKA D, CHARRON MJ (1998) Restoration of Hypoxia-stimulated Glucose Uptake in GLUT4-deficient Muscles by Muscle-specific GLUT4 Transgenic Complementation. J Biol Chem 273: 20910-20915         [ Links ]

ZIMMERMAN RL, GOONEWARDENE S, FOGT F (2001) Glucose transporter Glut-1 is of limited value for detecting breast carcinoma in serous effusions. Mod Pathol 14: 748-751         [ Links ]

ZORZANO A, SEVILLA L, CAMPS M, CECKER C, MEYER J, KAMMERMEIER H, MUÑOZ P, GUMA A, TESTAR X, PALACÍN M, BLASI J, FISCHER Y (1997) Regulation of glucose transport, and glucose trafficking in the heart: studies in cardiac myocytes. Am J Cardiol 80: 65A-76A         [ Links ]