The role of dysregulated glucose metabolism in epithelial ovarian cancer

Abstract

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer and also one of the most poorly understood. Other health issues that are affecting women with increasing frequency are obesity and diabetes, which are associated with dysglycemia and increased blood glucose. The Warburg Effect describes the ability of fast-growing cancer cells to preferentially metabolize glucose via anaerobic glycolysis rather than oxidative phosphorylation. Recent epidemiological studies have suggested a role for hyperglycemia in the pathogenesis of a number of cancers. If hyperglycemia contributes to tumour growth and progression, then it is intuitive that antihyperglycemic drugs may also have an important antitumour role. Preliminary reports suggest that these drugs not only reduce available plasma glucose, but also have direct effects on cancer cell viability through modification of molecular energy-sensing pathways. This review investigates the effect that hyperglycemia may have on EOC and the potential of antihyperglycemic drugs as therapeutic adjuncts.

Figure 1

Summary diagram of factors hypothesized to link hyperglycemia to the development of epithelial ovarian cancer. Hyperglycemia, leading to hyperinsulinemia and inflammation, underlies the development of parallel pathologies affecting growth and death signaling, formation of reactive species, and angiogenesis. Together, these aberrant signals converge on a hyperproliferative phenotype that may promote or initiate the development of cancer. Possible therapeutic approaches, including the novel application of antidiabetic drugs, are shown in green. Abbreviations: TZDs, thiazolidinedoines; GLUTs, facilitative glucose transporters; ROS, reactive oxygen species; NSAIDs, nonsteroidal antiinflammatory drugs; AGE-RAGE, advanced glycation end product receptor complex; IR-A and IR-B, insulin receptor isoforms A and B; IGF(R), insulin-like growth factor (receptor); cdk, cyclin-dependant kinase; TSP-1, thrombospondin-1; HIF-1α, hypoxia-inducible factor alpha; NF-κB, nuclear factor kappa B; VEGF, vascular endothelial growth factor.