PARK2 Depletion Connects Energy and Oxidative Stress to PI3K/Akt Activation via PTEN S-Nitrosylation

PARK2 is a gene implicated in disease states with opposing responses in cell fate determination, yet its contribution in pro-survival signaling is largely unknown. Here we show that PARK2 is altered in over a third of all human cancers, and its depletion results in enhanced phosphatidylinositol 3-kinase/Akt (PI3K/Akt) activation and increased vulnerability to PI3K/Akt/mTOR inhibitors. PARK2 depletion contributes to AMPK-mediated activation of endothelial nitric oxide synthase (eNOS), enhanced levels of reactive oxygen species, and a concomitant increase in oxidized nitric oxide levels, thereby promoting the inhibition of PTEN by S-nitrosylation and ubiquitination. Notably, AMPK activation alone is sufficient to induce PTEN S-nitrosylation in the absence of PARK2 depletion. Park2 loss and Pten loss also display striking cooperativity to promote tumorigenesis in vivo. Together, our findings reveal an important missing mechanism that might account for PTEN suppression in PARK2-deficient tumors, and they highlight the importance of PTEN S-nitrosylation in supporting cell survival and proliferation under conditions of energy deprivation.
We thank Rodrick Bronson, the entire HMS Rodent Histopathology Core, and the ICR Pathology Core for technical help with the mouse histopathology and discussions concerning the project. We also thank David Carling for the generous gift of the 991 activator, Nick Leslie for the pHR-SIN-PTEN-WT and Tina Yuan for the pLV430G-oFL-T2A-eGFP vectors, Pier Paolo Pandolfi for giving us access to Pten knockout (KO) mice, and Olga Corti and Alexis Brice for providing Park2 KO mice. We thank Susanne Breitkopf and Min Yuan for help with mass spectrometry. This work was supported by grants from the NIH P01-CA120964 (J.M.A. and L.C.C.) and R01-GM041890. A.V. was funded by the Ministry of Education, Culture and Sport under the Program for Promoting and Hiring of Talent and its Employability (Subprogram for Mobility) of the Spanish Government. G.P. is funded by the ICR. Work in the D.A. lab is supported by MRC grant MC_UP_1202/1. L.C.C. owns equity in, receives compensation from, and serves on the Board of Directors and Scientific Advisory Board of Agios Pharmaceuticals. Agios Pharmaceuticals is identifying metabolic pathways in cancer cells and developing drugs to inhibit such enzymes to disrupt tumor cell growth and survival. Finally, we would like to dedicate this work to the memory of Professor Chris Marshall who was an esteemed colleague and mentor, whose scientific discoveries will continue to inspire us and translate basic science into benefits for cancer patients.