title: Acetylation at lysine 71 inactivates superoxide dismutase 1 and sensitizes cancer cells to genotoxic agents.
abstract: Cancer cells are characterized by a high dependency on antioxidant enzymes to cope with the elevated rates of reactive oxygen species (ROS). Impairing antioxidant capacity in cancer cells disturbs the ROS homeostasis and exposes cancer cells to massive oxidative stress. In this study, we have discovered that superoxide dismutase 1 (SOD1), a major player in maintaining the cellular redox status, was acetylated at lysine 71. This acetylation, which was primarily deacetylated by Sirtuin 1 (SIRT1), suppressed the enzymatic activity of SOD1 via disrupting its association with copper chaperone for SOD1 (CCS). More importantly, genotoxic agents, such as camptothecin (CPT), induced SOD1 acetylation by disrupting its binding with SIRT1. CPT-induced SOD1 acetylation was stimulated by its provoked ROS, suggesting a positive feedback loop, in which ROS per se impairs the antioxidative defence of cancer cells and reinforces oxidative stress stimulated by anticancer agents. The intrinsic abundance of SOD1 acetylation varied among cancer cells, and high level of SOD1 acetylation was correlated with elevated sensitivity to CPT. Together, our findings gained mechanistic insights into how cytotoxic agents fine tune the intracellular ROS homeostasis to strengthen their anticancer effects, and suggested SOD1 acetylation as a candidate biomarker for predicting response to CPT-based chemotherapy.
authors.affiliation: Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.|National Nanjing New Drug Screening Center, China Pharmaceutical University, Nanjing, China.
authors.forename: Chenchu
authors.initials: C
authors.lastname: Lin
authors.affiliation: Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Hanlin
authors.initials: H
authors.lastname: Zeng
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Junyan
authors.initials: J
authors.lastname: Lu
authors.affiliation: Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Zuoquan
authors.initials: Z
authors.lastname: Xie
authors.affiliation: Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Wenyi
authors.initials: W
authors.lastname: Sun
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
authors.affiliation: Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
authors.affiliation: National Nanjing New Drug Screening Center, China Pharmaceutical University, Nanjing, China.
authors.forename: Shengtao
authors.initials: S
authors.lastname: Yuan
authors.affiliation: Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Meiyu
authors.initials: M
authors.lastname: Geng
authors.affiliation: Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Min
authors.initials: M
authors.lastname: Huang
mesh_terms: D000107:Acetylation; D000818:Animals; D002166:Camptothecin / Q000378:metabolism*; D045325:HCT116 Cells; D064593:Heterografts; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D051379:Mice; D018384:Oxidative Stress / Q000502:physiology; D017382:Reactive Oxygen Species; D056564:Sirtuin 1 / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
chemical_list: D017382:Reactive Oxygen Species; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D008239:Lysine; D002166:Camptothecin
keywords: SIRT1; acetylation; camptothecin; oxidative stress; superoxide dismutase