Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
ReviewExpression of glucose transporters in cancers
Introduction
Glucose is an essential metabolic substrate of all mammalian cells. It is not only as a precursor of glycoproteins, triglycerides, and glycogen. Glucose metabolism governs many functions, because the oxidation of glucose generates a major source of metabolic energy in eukaryotic cells. These functions are secondary to glucose uptake. 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 carrier proteins to mediate its specific transport into the cytosol. Glucose is transported into cells via two classes of hexose transporters: the SGLT (sodium-dependent glucose transporter) family and GLUT family. The SGLT family of transporters transports sugars against the concentration gradient utilizing the sodium-electrochemical gradient. The GLUT family are facilitative transporters that transport sugars along the concentration gradient [1]. After glucose enters normal cells, it is converted into pyruvate through glycolysis. Subsequently, pyruvate is transformed into acetyl-CoA, which is used as substrate in mitochondria to generate ATP.
Tumor cells exhibit an altered metabolism. Increased need for glycolysis, known as Warburg effect, and glucose uptake for ATP production and also lactate secretion is observed in tumor cells, particularly in cells lacking of oxygen supply. Hypoxia is a hallmark of cancer, upregulating GLUT expression [2].
Section snippets
Glucose metabolism in cancer
Tumor cells require a host vasculature for their supply of nutrients and oxygen, but oxygen cannot diffuse further than around 150 μm through tissues. As tumor growth outstrips its vasculature, the cells become hypoxic [3]. 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. A high level of hypoxia in solid tumors is an adverse prognostic factor for the poor outcome of
Human sodium glucose transporters (SGLT)
Sodium glucose transporters are also known as Na+/glucose transporters or symporters (SGLTs). Glucose transport is driven by the inward Na+ gradient maintained by the Na+ pump. There are 12 members of the human family (encoded by genes SLC5A1–SLC5A12), and they include Na+ cotransporters for sugars, myo-inositol, iodide, short fatty acids, and choline [10]. The human genome project ultimately led to the gene mapping of all six SGLTs beginning with SGLT1 on chromosome 22, SGLT2 16p12-p11, SGLT3
Facilitative glucose transport
A ubiquitous glucose transport also exists. LeFevre in 1948 was the first to postulate that a specific component within the cellular plasma membrane was required for the transfer of glucose across the lipid bilayer [20]. Facilitative glucose transporters (GLUTs) allow the energy independent transport of glucose across the hydrophobic cell membrane down its concentration gradient. The GLUT protein family belongs to the Major Facilitator Superfamily (MFS) of membrane transporters [21]. Well over
Expression of GLUT proteins in cancers
GLUT1 is a representative of the GLUT family and is widely distributed in normal tissues. This transporter is overexpressed in many tumors, including hepatic, pancreatic, breast, esophageal, brain, renal, lung, cutaneous, colorectal, endometrial, ovarian, and cervical cancers [25]. Several studies have shown a close relationship between GLUT1 expression, tumor development, and unfavourable prognosis of several tumors. The level of GLUT1 expression might be a suitable marker of hypoxia and
Potential role of sugar transporters in anticancer therapy
Many human cancers display a high rate of anaerobic glycolysis. Glucose utilization by cancer cells is therefore greatly enhanced when compared to normal or benign tissues. As described earlier, GLUT proteins are overexpressed in many human cancer cells. This overexpression is correlated with poor biological behavior. Although more than one GLUT may be expressed by a cell type, tumors frequently overexpress GLUT1, which is a high affinity glucose transporter. The inhibition of sugar transport
18F-FDG PET and PET/CT in cancer
PET (positron emission tomography) imaging with 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG) as a tracer is a non-invasive diagnostic and prognostic tool that measures tumor metabolism. Once 18F-FDG has entered the cell, it is subsequently phosphorylated to 2′-FDG-6-phosphate by the hexokinase enzyme. Phosphorylated product is not a substrate for the enzymes of the glycolytic pathway or the pentose-phosphate shunt. The content of the enzyme glucose-6-phosphatase, which could reverse the initial
Conclusions
Tumor cells exhibit enhanced glucose metabolism compared to normal tissue. The resulting large increase in glucose requirement implies a need for a corresponding increase in glucose transport across the plasma membrane. The majority of cancers overexpress 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
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