title: Desuccinylation of pyruvate kinase M2 by SIRT5 contributes to antioxidant response and tumor growth.
abstract: 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.
authors.affiliation: Department of Oncology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai 200030, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Xiangyun
authors.affiliation: Department of Oncology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai 200030, China.
authors.forename: Niu
authors.initials: N
authors.lastname: Xiaomin
authors.affiliation: Department of Oncology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai 200030, China.
authors.forename: Gu
authors.initials: G
authors.lastname: Linping
authors.affiliation: Department of Oncology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai 200030, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Yunhua
authors.affiliation: Department of Oncology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai 200030, China.
authors.forename: Li
authors.initials: L
authors.lastname: Ziming
authors.affiliation: Department of Oncology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai 200030, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yongfeng
authors.affiliation: Department of Oncology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai 200030, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhiwei
authors.affiliation: Department of Oncology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai 200030, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Shun
mesh_terms: D000072283:A549 Cells; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D049109:Cell Proliferation; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D037761:Sirtuins / Q000378:metabolism*; D013386:Succinates / Q000737:chemistry*; D013963:Thyroid Hormones / Q000737:chemistry / Q000378:metabolism*; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D002352:Carrier Proteins; D008239:Lysine; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; D037761:Sirtuins; D013386:Succinates; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins; C508544:SIRT5 protein, human
keywords: PKM2; ROS; SIRT5; succinylation; tumor growth