RRC ID 63214
Author Chong SJF, Iskandar K, Lai JXH, Qu J, Raman D, Valentin R, Herbaux C, Collins M, Low ICC, Loh T, Davids M, Pervaiz S.
Title Serine-70 phosphorylated Bcl-2 prevents oxidative stress-induced DNA damage by modulating the mitochondrial redox metabolism.
Journal Nucleic Acids Res
Abstract Bcl-2 phosphorylation at serine-70 (S70pBcl2) confers resistance against drug-induced apoptosis. Nevertheless, its specific mechanism in driving drug-resistance remains unclear. We present evidence that S70pBcl2 promotes cancer cell survival by acting as a redox sensor and modulator to prevent oxidative stress-induced DNA damage and execution. Increased S70pBcl2 levels are inversely correlated with DNA damage in chronic lymphocytic leukemia (CLL) and lymphoma patient-derived primary cells as well as in reactive oxygen species (ROS)- or chemotherapeutic drug-treated cell lines. Bioinformatic analyses suggest that S70pBcl2 is associated with lower median overall survival in lymphoma patients. Empirically, sustained expression of the redox-sensitive S70pBcl2 prevents oxidative stress-induced DNA damage and cell death by suppressing mitochondrial ROS production. Using cell lines and lymphoma primary cells, we further demonstrate that S70pBcl2 reduces the interaction of Bcl-2 with the mitochondrial complex-IV subunit-5A, thereby reducing mitochondrial complex-IV activity, respiration and ROS production. Notably, targeting S70pBcl2 with the phosphatase activator, FTY720, is accompanied by an enhanced drug-induced DNA damage and cell death in CLL primary cells. Collectively, we provide a novel facet of the anti-apoptotic Bcl-2 by demonstrating that its phosphorylation at serine-70 functions as a redox sensor to prevent drug-induced oxidative stress-mediated DNA damage and execution with potential therapeutic implications.
Volume 48(22)
Pages 12727-12745
Published 2020-12-16
DOI 10.1093/nar/gkaa1110
PII 6007660
PMID 33245769
PMC PMC7736805
MeSH Apoptosis / genetics Cell Proliferation / genetics Cisplatin / pharmacology DNA Damage / drug effects Doxorubicin / pharmacology Drug Resistance, Neoplasm / genetics Etoposide / pharmacology Fluorouracil / pharmacology Humans Jurkat Cells Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy* Leukemia, Lymphocytic, Chronic, B-Cell / genetics Leukemia, Lymphocytic, Chronic, B-Cell / pathology Lymphoma / drug therapy* Lymphoma / genetics Lymphoma / pathology Mitochondria / drug effects Mitochondria / genetics Mitochondria / metabolism* Oxidation-Reduction / drug effects Oxidative Stress / drug effects* Phosphorylation / drug effects Primary Cell Culture Proto-Oncogene Proteins c-bcl-2 / genetics* Reactive Oxygen Species / metabolism Serine / genetics
IF 11.502
Human and Animal Cells StromaNKtert(RCB2350)