Journal
ONCOTARGET
Volume 8, Issue 4, Pages 6984-6993Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.14346
Keywords
PKM2; succinylation; SIRT5; ROS; tumor growth
Categories
Funding
- National Natural Science Foundation of China Youth Project [81401878]
- Ministry of Science and Technology National International Cooperation of Science and Technology Special Project [2012DFG31320]
- Science and Technology Commission of Shanghai [12401907000, 11DZ1973203]
- Science and Technology Development Fund Major Key Projects of Shanghai Chest Hospital [2014YZDC10600]
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Tumor cells trends to express high level of pyruvate kinase M2 (PKM2). The inhibition of PKM2 activity is needed for antioxidant response by diverting glucose flux into the pentose phosphate pathway and thus generating sufficient reducing potential. Here we report that PKM2 is succinylated at lysine 498 (K498) and succinylation increases its activity. SIRT5 binds to, desuccinylates and inhibits PKM2 activity. Increased level of reactive oxygen species (ROS) decreases both the succinylation and activity of PKM2 by increasing its binding to SIRT5. Substitution of endogenous PKM2 with a succinylation mimetic mutant K498E decreases cellular NADPH production and inhibits cell proliferation and tumor growth. Moreover, inhibition of SIRT5 suppresses tumor cell proliferation through desuccinylation of PKM2 K498. These results reveal a new mechanism of PKM2 modification, a new function of SIRT5 in response to oxidative stress which stimulates cell proliferation and tumor growth, and also a potential target for clinical cancer research.
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