Dr. Michelakis May 2012 paper published in Oncogene
Oncogene , (21 May 2012) | doi:10.1038/onc.2012.198
Mitochondrial activation by inhibition of PDKII suppresses HIF1a signaling and angiogenesis in cancer
G Sutendra, P Dromparis, A Kinnaird, T H Stenson, A Haromy, J M R Parker, M S McMurtry and E D Michelakis
Due in part to intentionally inhibited mitochondrial function, which favors resistance to apoptosis, the majority of solid tumors exhibit a metabolic shift from glucose oxidation to glycolysis. Hypoxia-inducible factor 1 (HIF1) and angiogenesis may both be triggered by suppressed mitochondrial function. In the past, we have demonstrated that the PDK inhibitor dichloroacetate (DCA) promotes glucose oxidation and causes death in cancer cells both in vitro and in vivo. We proposed that DCA will also suppress cancer angiogenesis and reverse the “pseudohypoxic” mitochondrial signals that trigger HIF1 activation in cancer, even in the absence of hypoxia. Using a variety of methods, such as HIF1 luciferase reporter assays, we demonstrate that PDKII inhibition decreases HIF1 in cancer cells. We demonstrate that DCA inhibits HIF1 by both a PHD-dependent mechanism (that involves a DCA-induced increase in the production of mitochondrial-derived -ketoglutarate) and a PHD-independent mechanism, involving activation of p53 via mitochondrial-derived H2O2 as well as activation of GSK3. This inhibition of HIF1 by DCA is mediated by both of these mechanisms. Both a decrease in the expression of various HIF1-regulated gene products and a suppression of in vitro angiogenesis in matrigel experiments demonstrate effective inhibition of HIF1. More significantly, we demonstrate efficient angiogenesis and tumor perfusion suppression in vivo in rat xenotransplant models of non-small cell lung cancer and breast cancer, as determined by contrast-enhanced ultrasonography, nuclear imaging methods, and histology. This work suggests that, in addition to the recently described pro-apoptotic and anti-proliferative effects, mitochondria-targeting metabolic modulators that increase pyruvate dehydrogenase activity also suppress angiogenesis, normalizing the pseudo-hypoxic signals that result in normoxic HIF1 activation in solid tumors.