Ovarian cancer is the deadliest gynecological malignancy worldwide. Although chemotherapy is required as the most standard treatment strategy for ovarian cancer, the survival rates are very low, largely because of high incidence of recurrence due to resistance to conventional surgery and genotoxic chemotherapies. Carboplatin-resistant ovarian cancer cells were generated by continuous treatment over six months. Carboplatin-resistance induced morphological alterations and promoted the rates of proliferation and migration of SKOV3 compared to the parental cells. Interestingly, carboplatin-resistant SKOV3 showed the high levels of γH2AX foci formed at the basal level, and the levels of γH2AX foci remained even after the recovery time, suggesting that the DNA damage response and repair machinery were severely attenuated by carboplatin-resistance. Surprisingly, the expression levels of XRCC4, a critical factor in non-homologous end joining (NHEJ) DNA repair, were significantly decreased in carboplatin-resistant SKOV3 compared with those in non-resistant controls. Furthermore, restoration of NHEJ in carboplatin-resistant SKOV3 by suppression of ABCB1 and/or AR re-sensitized carboplatin-resistant cells to genotoxic stress and reduced their proliferation ability. Our findings suggest that attenuation of the NHEJ DNA repair machinery mediated by resistance to genotoxic stress might be a critical cause of chemoresistance in patients with ovarian cancer.

卵巢癌是全球最致命的妇科恶性肿瘤。尽管需要化疗作为卵巢癌最标准的治疗策略，但存活率非常低，这主要是由于对常规手术和基因毒性化学疗法的耐药性导致复发率高。通过持续治疗六个月以上产生了耐卡铂的卵巢癌细胞。与亲代细胞相比，卡铂耐药性诱导了形态学改变并促进了 SKOV3 的增殖和迁移率。有趣的是，耐卡铂的 SKOV3 显示在基础水平形成高水平的 γH2AX 病灶，即使在恢复时间之后，γH2AX 病灶的水平仍然存在，这表明 DNA 损伤反应和修复机制被卡铂耐药性严重削弱。令人惊讶的是，与非抗性对照相比，抗卡铂 SKOV3 中非同源末端连接 (NHEJ) DNA 修复的关键因素 XRCC4 的表达水平显着降低。此外，通过抑制 ABCB1 和/或 AR 在耐卡铂 SKOV3 中恢复 NHEJ 使耐卡铂细胞对基因毒性应激重新敏感并降低其增殖能力。我们的研究结果表明，由对基因毒性应激的抗性介导的 NHEJ DNA 修复机制的减弱可能是卵巢癌患者化学抗性的一个关键原因。通过抑制 ABCB1 和/或 AR 恢复耐卡铂 SKOV3 中的 NHEJ 使耐卡铂细胞对基因毒性应激重新敏感并降低其增殖能力。我们的研究结果表明，由对基因毒性应激的抗性介导的 NHEJ DNA 修复机制的减弱可能是卵巢癌患者化学抗性的一个关键原因。通过抑制 ABCB1 和/或 AR 恢复耐卡铂 SKOV3 中的 NHEJ 使耐卡铂细胞对基因毒性应激重新敏感并降低其增殖能力。我们的研究结果表明，由对基因毒性应激的抗性介导的 NHEJ DNA 修复机制的减弱可能是卵巢癌患者化学抗性的一个关键原因。