| RRC ID |
63214
|
| 著者 |
Chong SJF, Iskandar K, Lai JXH, Qu J, Raman D, Valentin R, Herbaux C, Collins M, Low ICC, Loh T, Davids M, Pervaiz S.
|
| タイトル |
Serine-70 phosphorylated Bcl-2 prevents oxidative stress-induced DNA damage by modulating the mitochondrial redox metabolism.
|
| ジャーナル |
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.
|
| 巻・号 |
48(22)
|
| ページ |
12727-12745
|
| 公開日 |
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
|
| リソース情報 |
| ヒト・動物細胞 |
StromaNKtert(RCB2350) |
