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Biological Research

Print version ISSN 0716-9760

Biol. Res. vol.35 no.1 Santiago  2002 

Glucose transporters: expression, regulation and cancer


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:

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


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


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.



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.

Tissue-specific expression of the GLUT family members.

Protein Alias Expression Function Reference


All tissues (abundant in brain
and erythrocytes)

Basal uptake Mueckler et al, 1985

Liver, pancreatic islet cells,

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,
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)



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


Over-expressed Associated Chang et al, 2000


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


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


Over-expressed NR Binder et al, 1997


Over-expressed Associated Airley et al, 2001


Over-expressed Associated Sakashita et al, 2001


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


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


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


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


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


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).


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).


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


Glut 2 Over-expressed Associated Noguchi et al, 1999



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


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


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


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


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


Glut 3 Over-expressed NR Glick 1993



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


Glut 4 Over-expressed NR Binder et al, 1997


Glut 4 Over-expressed NR Noguchi et al, 1999


Glut 4 Over-expressed NR Ito et al, 1998



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.


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).


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


HOS Glut 1 (presumed) Waki et al, 1998


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


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


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


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


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


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


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


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


LS180 Glut1 Fujibayashi et al, 1997


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


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


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


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


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


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


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



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).

Regulators and signaling pathways involved in glucose transport.


Pathway GLUT Isoform Cell type Reference


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


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


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


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


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.


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.


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