Department of Biomedical Science, School of Life Science, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, South Korea.
Department of Biochemistry, Research Institute for Basic Medical Science, School of Medicine, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, South Korea.
Cancer Lett. 2021 Nov 1;520:267-280. doi: 10.1016/j.canlet.2021.08.003. Epub 2021 Aug 8.
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.
卵巢癌是全球致死率最高的妇科恶性肿瘤。尽管化疗是治疗卵巢癌最标准的策略，但存活率非常低，这主要是由于对传统手术和遗传毒性化疗的耐药性导致高复发率。通过连续治疗六个月以上，生成了对卡铂耐药的卵巢癌细胞。与亲本细胞相比，卡铂耐药诱导了 SKOV3 细胞形态的改变，并促进了其增殖和迁移的速度。有趣的是，卡铂耐药的 SKOV3 细胞在基础水平上形成了大量的 γH2AX 焦点，即使在恢复时间后，其 γH2AX 焦点水平仍然保持不变，这表明 DNA 损伤反应和修复机制被卡铂耐药严重削弱。令人惊讶的是，与非耐药对照组相比，卡铂耐药的 SKOV3 中关键的非同源末端连接（NHEJ）DNA 修复因子 XRCC4 的表达水平显著降低。此外，通过抑制 ABCB1 和/或 AR 抑制来恢复 NHEJ，可使卡铂耐药细胞对遗传毒性应激重新敏感，并降低其增殖能力。我们的研究结果表明，对遗传毒性应激的耐药性介导的 NHEJ DNA 修复机制的衰减可能是卵巢癌患者化疗耐药的一个关键原因。
