Clinical Experimental Center, Jiangmen Key Laboratory of Clinical Biobanks and Translational Research, Jiangmen Central Hospital, Jiangmen, 529030, China.
Department of Gynecology, Jiangmen Central Hospital, Jiangmen, 529030, China.
Cell Death Dis. 2023 Aug 26;14(8):568. doi: 10.1038/s41419-023-06084-5.
Sustained activation of DNA damage response (DDR) signaling has been demonstrated to play vital role in chemotherapy failure in cancer. However, the mechanism underlying DDR sustaining in cancer cells remains unclear. In the current study, we found that the expression of the DDUP microprotein, encoded by the CTBP1-DT lncRNA, drastically increased in cisplatin-resistant ovarian cancer cells and was inversely correlated to cisplatin-based therapy response. Using a patient-derived human cancer cell model, we observed that DNA damage-induced DDUP foci sustained the RAD18/RAD51C and RAD18/PCNA complexes at the sites of DNA damage, consequently resulting in cisplatin resistance through dual RAD51C-mediated homologous recombination (HR) and proliferating cell nuclear antigen (PCNA)-mediated post-replication repair (PRR) mechanisms. Notably, treatment with an ATR inhibitor disrupted the DDUP/RAD18 interaction and abolished the effect of DDUP on prolonged DNA damage signaling, which resulted in the hypersensitivity of ovarian cancer cells to cisplatin-based therapy in vivo. Altogether, our study provides insights into DDUP-mediated aberrant DDR signaling in cisplatin resistance and describes a potential novel therapeutic approach for the management of platinum-resistant ovarian cancer.
持续激活 DNA 损伤反应 (DDR) 信号已被证明在癌症的化疗失败中发挥重要作用。然而，癌细胞中 DDR 持续存在的机制仍不清楚。在本研究中，我们发现 CTBP1-DT lncRNA 编码的 DDUP 微蛋白的表达在顺铂耐药卵巢癌细胞中急剧增加，并且与基于顺铂的治疗反应呈负相关。使用患者来源的人类癌细胞模型，我们观察到 DNA 损伤诱导的 DDUP 焦点在 DNA 损伤部位维持 RAD18/RAD51C 和 RAD18/PCNA 复合物，从而通过 RAD51C 介导的同源重组 (HR) 和增殖细胞核抗原 (PCNA) 介导的复制后修复 (PRR) 机制导致顺铂耐药。值得注意的是，ATR 抑制剂的治疗破坏了 DDUP/RAD18 相互作用，并消除了 DDUP 对延长 DNA 损伤信号的影响，导致卵巢癌细胞对基于顺铂的治疗在体内产生超敏反应。总之，我们的研究提供了 DDUP 介导的顺铂耐药中异常 DDR 信号的见解，并描述了一种管理铂耐药卵巢癌的潜在新治疗方法。
