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 K_m 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 K_m 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 K_m 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 (k_in) and one for externalization (k_ex). Insulin causes transporter translocation by reducing k_in and increasing k_ex 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 K_m 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 G_q 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.

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