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

Date
2017-03ICR Author
Author
Gupta, A
Anjomani-Virmouni, S
Koundouros, N
Dimitriadi, M
Choo-Wing, R
Valle, A
Zheng, Y
Chiu, Y-H
Agnihotri, S
Zadeh, G
Asara, JM
Anastasiou, D
Arends, MJ
Cantley, LC
Poulogiannis, G
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
HCT116 Cells
Animals
Mice, Inbred NOD
Mice, Knockout
Humans
Mice, SCID
Neoplasms
Nitric Oxide
Ubiquitin-Protein Ligases
Antineoplastic Agents
Protein Kinase Inhibitors
Tumor Burden
Gene Expression Profiling
Transfection
Signal Transduction
Cell Proliferation
Cell Movement
Cell Survival
Gene Expression Regulation, Neoplastic
RNA Interference
Protein Processing, Post-Translational
Enzyme Activation
Energy Metabolism
Oxidation-Reduction
Oxidative Stress
Dose-Response Relationship, Drug
Time Factors
Proto-Oncogene Proteins c-akt
PTEN Phosphohydrolase
Nitric Oxide Synthase Type III
Ubiquitination
AMP-Activated Protein Kinases
HEK293 Cells
Phosphatidylinositol 3-Kinase
TOR Serine-Threonine Kinases
MCF-7 Cells
Phosphoinositide-3 Kinase Inhibitors
Research team
Signalling & Cancer Metabolism
Language
eng
Date accepted
2017-02-17
License start date
2017-03
Citation
Molecular cell, 2017, 65 (6), pp. 999 - 1013.e7
Except where otherwise noted, this item's license is described
as
https://creativecommons.org/licenses/by/4.0
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