Inhibition of BRCT(BRCA1)-phosphoprotein interaction enhances the cytotoxic effect of olaparib in breast cancer cells: a proof of concept study for synthetic lethal therapeutic option.
Inhibition of BRCT(BRCA1)-phosphoprotein interaction enhances the cytotoxic effect of olaparib in breast cancer cells: a proof of concept study for synthetic lethal therapeutic option.
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DOI：
10.1007/s10549-012-2079-4
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发表时间：
2012-07
影响因子：
3.8
通讯作者：
Natarajan, Amarnath
中科院分区：
文献类型：
--
作者：
Pessetto, Ziyan Yuan;Yan, Ying;Bessho, Tadayoshi;Natarajan, Amarnath
使用聚（腺苷二磷酸 [ADP]-核糖）聚合酶 (PARP) 抑制剂奥拉帕尼治疗 BRCA1 或 BRCA2 突变携带者的合成致死治疗策略已在临床环境中显示出前景。由于 < 5% 的患者是 BRCA1 或 BRCA2 突变携带者，功能上模拟 BRCA1 或 BRCA2 突变的小分子将扩大非突变携带者的合成致死治疗选择。在这里，我们使用 BRCA1 抑制剂肽 2 提供了该策略的原理证明，该肽 2 靶向 BRCT(BRCA1)-磷蛋白相互作用并模拟 M177R/K BRCA1 突变。 BRCA1 和 Abraxas 的相互免疫沉淀和免疫印迹用于证明抑制剂 2 靶向 BRCT(BRCA1)-Abraxas 界面。进行 γH2AX 免疫染色、细胞周期分析和同源重组 (HR) 测定，以确认抑制剂 2 在功能上模拟化学增敏 BRCA1 突变。在 HeLa、MDA-MB-231 和 HCC1937 细胞系中探索了使用 BRCA1 抑制剂 2 和 PARP 抑制剂 Olaparib 的合成致死治疗策略的概念。结果表明，BRCA1 2 的抑制使 HeLa 和 MDA-MB-231 细胞对奥拉帕尼介导的生长抑制和凋亡敏感，但对 HCC1937 细胞不敏感。这些结果为开发高亲和力 BRCT(BRCA1) 抑制剂作为治疗散发性乳腺癌和卵巢癌的佐剂提供了基础。
Synthetic lethal therapeutic strategy using poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor Olaparib in carriers of BRCA1 or BRCA2 mutation has shown promise in clinical settings. Since < 5% of patients are BRCA1 or BRCA2 mutation carriers, small molecules that functionally mimic BRCA1 or BRCA2 mutations will extend the synthetic lethal therapeutic option for non-mutation carriers. Here we provide proof of principle for this strategy using a BRCA1 inhibitor peptide 2 that targets the BRCT(BRCA1)-phosphoprotein interaction and mimics the M177R/K BRCA1 mutation. Reciprocal immunoprecipitation and immunoblotting of BRCA1 and Abraxas was used to demonstrate inhibitor 2 targets BRCT(BRCA1)-Abraxas interface. Immunostaining of γH2AX, cell cycle analysis and homologous recombination (HR) assays were conducted to confirm that inhibitor 2 functionally mimics a chemosensitizing BRCA1 mutation. The concept of synthetic lethal therapeutic strategy with the BRCA1 inhibitor 2 and the PARP inhibitor Olaparib was explored in HeLa, MDA-MB-231, and HCC1937 cell lines. The results show that inhibition of BRCA1 by 2 sensitizes HeLa and MDA-MB-231 cells but not HCC1937 to Olaparib mediated growth inhibition and apoptosis. These results provide the basis for developing high affinity BRCT(BRCA1) inhibitors as adjuvants to treat sporadic breast and ovarian cancers.
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