Serine-70 phosphorylated Bcl-2 prevents oxidative stress-induced DNA damage by modulating the mitochondrial redox metabolism

Nucleic Acids Res. 2020 Dec 16;48(22):12727-12745. doi: 10.1093/nar/gkaa1110.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • BCL2 protein, human
  • Proto-Oncogene Proteins c-bcl-2
  • Reactive Oxygen Species
  • Serine
  • Etoposide
  • Doxorubicin
  • Cisplatin
  • Fluorouracil