論文 - 詳細
| 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 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 8 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | StromaNKtert(RCB2350) |