Mitochondrial Akt Regulation of Hypoxic Tumor Reprogramming Young Chan Chae1, 2, M. Cecilia Caino1, and Dario C. Altieri1 1Prostate Cancer Discovery and Development Program, Tumor Microenvironment and Metastasis Program, Wistar Institute, Philadelphia, PA 19104, USA 2School of Life Science, Ulsan National Institute of Science and Technology(UNIST), Ulsan, 44919, South Korea
One of main characteristics of cancer cell is their fast proliferation. As such, rapidly growing tumors are constantly exposed to unfavorable growth conditions on the tumor environment including nutrient deprivation, acidosis and hypoxia. Tumor cells avoid cell death through adaptive mitochondrial pathways that support rapid cell growth and buffer metabolic stress for. However, it is still unknown how metabolic pathways of tumor are regulated and successfully adapt to environmental stress. Here, we show that chaperones compartmentalized in mitochondria are required to regulating tumor bioenergetics, adaptation to cellular stress and cell survival. Interference with this process activates a signaling network that involves phosphorylation of nutrient-sensing AMP-activated kinase (AMPK), inhibition of rapamycin-sensitive mTOR complex 1 (mTORC1), and induction of autophagy. Furthermore, using a phosphoproteomics screen, we show that active Akt accumulates in the mitochondria during hypoxia and phosphorylates pyruvate dehydrogenase kinase 1 (PDK1) on Thr346 to inactivate the pyruvate dehydrogenase complex. In turn, this pathway switches tumor metabolism towards glycolysis, antagonizes apoptosis and autophagy, dampens oxidative stress, and maintains tumor cell proliferation in the face of severe hypoxia. Mitochondrial Akt-PDK1 signaling correlates with unfavorable prognostic markers and shorter survival in glioma patients. Taken together, this study will accelerate research to understand metabolism of tumors and can provide improved cancer therapy.
References Chae et al. Cancer Cell. 2016 Aug 8;30(2):257-272. doi: 10.1016/j.ccell.2016.07.004.