title: PARK2 Depletion Connects Energy and Oxidative Stress to PI3K/Akt Activation via PTEN S-Nitrosylation.
abstract: 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.
authors.affiliation: Signalling and Cancer Metabolism Team, Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
authors.forename: Amit
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Signalling and Cancer Metabolism Team, Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Anjomani-Virmouni
authors.affiliation: Signalling and Cancer Metabolism Team, Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK; Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, London SW7 2AZ, UK.
authors.forename: Nikos
authors.initials: N
authors.lastname: Koundouros
authors.affiliation: Signalling and Cancer Metabolism Team, Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK; Department of Biological and Environmental Sciences, University of Hertfordshire, Hatfield AL10 9AB, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Dimitriadi
authors.affiliation: Novartis Institutes for BioMedical Research, Inc., 181 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Rayman
authors.initials: R
authors.lastname: Choo-Wing
authors.affiliation: Signalling and Cancer Metabolism Team, Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK; Energy Metabolism and Nutrition, University of Balearic Islands, Research Institute of Health Sciences (IUNICS) and Medical Research Institute of Palma (IdISPa), 07122 Palma de Mallorca, Spain; Biomedical Research Networking Center for Physiopathology of Obesity and Nutrition (CIBERobn), Instituto de Salud Carlos III, 28029 Madrid, Spain.
authors.forename: Adamo
authors.initials: A
authors.lastname: Valle
authors.affiliation: Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Novartis Institutes for BioMedical Research, Inc., 22 Windsor Street, Cambridge, MA 02139, USA.
authors.forename: Yu-Hsin
authors.initials: YH
authors.lastname: Chiu
authors.affiliation: MacFeeters-Hamilton Neurooncology Program, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada.
authors.forename: Sameer
authors.initials: S
authors.lastname: Agnihotri
authors.affiliation: MacFeeters-Hamilton Neurooncology Program, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada.
authors.forename: Gelareh
authors.initials: G
authors.lastname: Zadeh
authors.affiliation: Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02175, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.affiliation: Cancer Metabolism Laboratory, The Francis Crick Institute, London NW7 1AA, UK.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Anastasiou
authors.affiliation: University of Edinburgh, Division of Pathology, Edinburgh Cancer Research Centre, Institute of Genetics & Molecular Medicine, Western General Hospital, Edinburgh EH4 2XR, UK.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Arends
authors.affiliation: Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address: lcantley@med.cornell.edu.
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.affiliation: Signalling and Cancer Metabolism Team, Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK; Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, London SW7 2AZ, UK. Electronic address: george.poulogiannis@icr.ac.uk.
authors.forename: George
authors.initials: G
authors.lastname: Poulogiannis
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism; D004789:Enzyme Activation; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency* / Q000235:genetics; D054875:Ubiquitination
chemical_list: D000970:Antineoplastic Agents; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D009569:Nitric Oxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse
keywords: AMPK; PARK2, PI3K/Akt activation; PTEN; S-nitrosylation; nitric oxide