Hypoxic Regulation of Glucose Transport, Anaerobic Metabolism and Angiogenesis in Cancer: Novel Pathways and Targets for Anticancer Therapeutics

Abstract

Cancer cells require a steady source of metabolic energy in order to continue their uncontrolled growth and proliferation. Accelerated glycolysis is one of the biochemical characteristics of cancer cells. Recent work indicates that glucose transport and metabolism are essential for the posttreatment survival of tumor cells, leading to poor prognosis. Glycolytic breakdown of glucose is preceded by the transport of glucose across the cell membrane, a rate-limiting process mediated by facilitative glucose transporter proteins belonging to the facilitative glucose transporter/solute carrier GLUT/SLC2A family. Tumors frequently show overexpression of GLUTs, especially the hypoxia-responsive GLUT1 and GLUT3 proteins. There are also studies that have reported associations between GLUT expression and proliferative indices, whilst others suggest that GLUT expression may be of prognostic significance. In this article we revisit Warburg’s original hypothesis and review the recent clinical and basic research on the expression of GLUT family members in human cancers and in cell lines derived from human tumors. We also explore the links between hypoxia-induced genes, glucose transporters and angiogenic factors. Hypoxic tumors are significantly more malignant, metastatic, radio- and chemoresistant and have a poor prognosis. With the discovery the oxygen-sensitive transcription factor hypoxia-inducible factor (HIF-1) has come a new understanding of the molecular link between hypoxia and deregulated glucose metabolism. HIF-1 induces a number of genes integral to angiogenesis, e.g. vascular endothelial growth factor (VEGF), a process intimately involved with metastatic spread. This knowledge may enhance existing chemotherapeutic strategies so that treatment can be more rationally applied and personalized for cancer patients.

miR-186 Regulates Glycolysis through Glut1 During the Formation of Cancer-associated Fibroblasts

“…Previous study showed Glut1 expression was regulated by hypoxia, and HIF-1α might be involved in this regulation (Airley et al, 2007). Our data have demonstrated that the expression of Glut1 is regulated by miR-186, and downregulation of miR-186 increases glucose uptake and lactate production through upregulation of Glut1 during CAF formation.…”

Induction of the Warburg effect by Kaposi's sarcoma herpesvirus is required for the maintenance of latently infected endothelial cells

“…Glucose transporter 3 (GLUT3) is induced in many cancer cells lines, as well as during hypoxia, and is responsible for increased glucose uptake (14). GLUT3 protein levels are greatly increased in endothelial cells latently infected with KSHV as determined by Western blot analysis with anti-GLUT3 antibodies (Fig.…”

Mechanism of inhibition of human glucose transporter GLUT1 is conserved between cytochalasin B and phenylalanine amides

“…Cancerous cells grow and multiply faster than normal cells, resulting in an acutely increased demand for energy (6). The up-regulation of hGLUT1 upon increased demand for glucose highlights it as an important prognostic indicator in several cancer types (7)(8)(9)(10), as well as a potential new target for therapeutic inhibitors.…”