Inactivation of the HIF-1α/PDK3 Signaling Axis Drives Melanoma toward Mitochondrial Oxidative Metabolism and Potentiates the Therapeutic Activity of Pro-Oxidants

Abstract

Cancer cells can undergo a metabolic reprogramming from oxidative phosphorylation to glycolysis that allows them to adapt to nutrient-poor microenvironments, thereby imposing a selection for aggressive variants. However, the mechanisms underlying this reprogramming are not fully understood. Using complementary approaches in validated cell lines and freshly obtained human specimens, we report here that mitochondrial respiration and oxidative phosphorylation are slowed in metastatic melanomas, even under normoxic conditions due to the persistence of a high nuclear expression of hypoxia-inducible factor-1a (HIF-1a). Pharmacologic or genetic blockades of the HIF-1a pathway decreased glycolysis and promoted mitochondrial respiration via specific reduction in the expression of pyruvate dehydrogenase kinase-3 (PDK3). Inhibiting PDK3 activity by dichloroacetate (DCA) or siRNA-mediated attenuation was sufficient to increase pyruvate dehydrogenase activity, oxidative phosphorylation, and mitochondrial reactive oxygen species generation. Notably, DCA potentiated the antitumor effects of elesclomol, a pro-oxidative drug currently in clinical development, both by limiting cell proliferation and promoting cell death. Interestingly, this combination was also effective against BRAF V600E-mutant melanoma cells that were resistant to the BRAF inhibitor vemurafenib. Cotreatment of melanomas with DCA and elesclomol in vivo achieved a more durable response than single agent alone. Our findings offer a preclinical validation of the HIF-1/PDK3 bioenergetic pathway as a new target for therapeutic intervention in metastatic melanoma, opening the door to innovative combinations that might eradicate this disease. Cancer Res; 72(19); 5035-47. Ó2012 AACR.

The BRAF Inhibitor Vemurafenib Activates Mitochondrial Metabolism and Inhibits Hyperpolarized Pyruvate–Lactate Exchange in BRAF-Mutant Human Melanoma Cells

“…Indeed, we observed increased ROS production (to a similar extent as in previous publications; ref. 33) following treatment with vemurafenib, indicating that the drug may also be activating OxPhos in our model, in agreement with earlier findings (16,34).…”

Glucose-independent Acetate Metabolism Promotes Melanoma Cell Survival and Tumor Growth

“…Surprisingly, exposure to 0.55 mM DNP was not cytotoxic to melanoma cells and the DNP treatment caused an increase in ATP levels suggesting a metabolic adaptation to glycolysis (9). Several studies have shown that melanoma cells poorly respond to protonophore FCCP and are highly resistant to cytotoxic effects of OXPHOS inhibitors (47,48). These observations are consistent with the findings that the development of resistance to BRAF inhibition was associated with gain of mitochondrial functions (9 -12).…”

miR-33a functions as a tumor suppressor in melanoma by targeting HIF-1α

“…33 C-1311 is a better inhibitor for HIF-1a pathway inhibitor to exhibit better anti-tumor effects. 34 MicroRNA interference technique can effectively inhibit the progress of melanoma invasion.…”