Inhibition of Rad51 sensitizes breast cancer cells with wild-type PTEN to olaparib
| Autor: | Likun Liu, Zhiwei Zhang, Qian Zhao, Qi Zhou, Yulu Wang, Jian Lv, Jiawei Guan, Weifeng Mao |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
DNA Repair Tumor suppressor gene DNA repair DNA damage Breast Neoplasms Piperazines Olaparib 03 medical and health sciences chemistry.chemical_compound PARP1 Cell Line Tumor Humans PTEN Pharmacology biology PTEN Phosphohydrolase General Medicine Molecular biology Up-Regulation Comet assay 030104 developmental biology chemistry Drug Resistance Neoplasm Cancer cell biology.protein Cancer research Phthalazines Female Rad51 Recombinase DNA Damage |
| Zdroj: | Biomedicine & Pharmacotherapy. 94:165-168 |
| ISSN: | 0753-3322 |
| Popis: | PTEN is a tumor suppressor gene well characterized as a phosphatase. However, more evidences demonstrate PTEN functions in DNA repair independent of its phosphatase activity, which affects the efficacy of DNA damage anti-tumoral drugs in treating cancer cells with PTEN variations. Using BT549 breast cancer cells, we studied the roles of PTEN in DNA repair and in sensitization of breast cancer cells to olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor. Comet assay showed PTEN promoted DNA repair. PTEN-deficient BT549 cells are sensitive to olaparib, which shows the synthetic lethality between PTEN and PARP1. We expressed PTEN in BT549 cells and found PTEN-proficient BT549 cells resist to olaparib. Western blot showed that PTEN up-regulated Rad51 expression, suggesting PTEN promotes DNA repair through Rad51-dependnent homologous recombination. We used 5μM olaparib or 5μM RI-1, a Rad51 inhibitor, to treat PTEN-proficient BT549 cells respectively. The immunofluorescent analysis showed the combination of olaparib and RI-1 induced more than 4-fold of γH2AX foci than either of them. MTT assay showed 5μM RI-1 did not change the survival of PTEN-proficient BT549 cells, however, this dose of RI-1 sensitized PTEN-proficient BT549 cells to olaparib. Consequently, these results demonstrate that inhibition of Rad51 can sensitize BT549 cells with wild type PTEN to olaparib, which would contribute to using PARP inhibitors in individual treatment of breast cancer patients with PTEN variations. |
| Databáze: | OpenAIRE |
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