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.