The Causes and Consequences of Altered Glucose Metabolism in Cancer
Uniformed Services University Of The Health Sciences Bethesda United States
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Altered glucose metabolism as reflected by lactate accumulation despite adequate oxygen availability is commonly associated with malignant transformation. However, the causes and consequences of this link remain unclear. Here we explore possible causes of this metabolic pattern and how they may promote malignancy. The transcription factor Hypoxia Inducible Factor-1 HIF-1 controls the expression of many genes commonly associated with malignancy, including those which increase lactate, and its activation in cancer is highly correlated with poor clinical outcome. HIF-1 activation by hypoxia is well characterized however, its regulation under normoxia in cancer cells is still uncertain. Here we show that elevated glucose metabolites promote normoxic HIF-1 activation via inhibition of its degradation pathway. Since HIF-1 activation results in elevation of the glucose metabolites that inhibit its degradation, we suggest a novel feed-forward mechanism of malignant progression. HIF-1activation has also been shown to alter glucose metabolism through inhibition of the Pyruvate Dehydrogenase Complex PDC. The PDC is inhibited by phosphorylation of its regulatory PDHalpha subunit, and HIF-1 increases phosphorylation through expression of Pyruvate Dehydrogenase Kinase-1 PDK-1. Here we show that increased PDHalpha phosphorylation and PDK-1 expression are associated with malignancy and normoxic HIF-1 accumulation in cancer cells. Furthermore, we show that inhibition of PDK expression by short hairpin RNA shRNA results in reversion from the malignant phenotype and normoxic HIF-1 accumulation in cancer cells both in vitro and in vivo. The link between HIF-1, glucose metabolism, PDC activity and the malignant phenotype suggests a novel regulatory pathway and further signifies the importance of abnormal glucose metabolism in malignancy.