Department of Gynecologic Oncology, Hunan Cancer Hospital, the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, PR China.
Department of Gynecology and Obstetrics, Shaoyang Central Hospital, Shaoyang 422000, PR China.
Exp Cell Res. 2022 Jan 15;410(2):112935. doi: 10.1016/j.yexcr.2021.112935. Epub 2021 Dec 4.
Resistance to platinum and PARP inhibitors represents a major barrier to the long-term survival of ovarian cancer patients. We aim to explore the potential role of chronic stress in drug resistance in ovarian cancer. Leveraging four ovarian cancer with chronic stress (OCCS) mouse models, we explore the therapeutic efficacy of platinum, Niraparib, and Docetaxel treatment in vivo, and compare the efficacy of these anti-tumor drugs in vitro using cell viability assays. Comparing the transcriptional characteristics in RNA-Seq of OCCS mice with public databases, we analyze the molecular mechanism of chronic stress promoting drug resistance in ovarian cancer. We find that chronic stress is positively correlated with platinum-resistant recurrence in ovarian cancer patients. Chronic stress can induce platinum and Niraparib resistance of ovarian cancer, but it does not affect the therapeutic efficacy of Docetaxel treatment in vivo. And the platinum-resistant cell lines are not sensitive to these anti-tumor drugs, which is different from the result in vivo. Then, we identify several gene networks and their constituent genes that are most significantly associated with chronic stress and drug resistance in ovarian cancer, including the glycolysis pathway and DNA damage. This study develops Niraparib and platinum-resistant in vivo models, reflecting the ability of OCCS mice to reproduce different aspects of human ovarian cancer molecular mechanism, and provides a new theoretical basis for overcoming the double drug resistance of ovarian cancer.
铂类药物和 PARP 抑制剂耐药是卵巢癌患者长期生存的主要障碍。我们旨在探讨慢性应激在卵巢癌耐药中的潜在作用。利用四个具有慢性应激（OCCS）的卵巢癌小鼠模型，我们在体内探索铂类药物、尼拉帕利和多西他赛治疗的疗效，并通过细胞活力测定比较这些抗肿瘤药物在体外的疗效。通过将 OCCS 小鼠的 RNA-Seq 转录特征与公共数据库进行比较，我们分析了慢性应激促进卵巢癌耐药的分子机制。我们发现慢性应激与卵巢癌铂类耐药复发呈正相关。慢性应激可诱导卵巢癌对铂类和尼拉帕利产生耐药性，但不影响多西他赛在体内的治疗效果。而且，铂类耐药细胞系对这些抗肿瘤药物不敏感，这与体内结果不同。然后，我们确定了几个与卵巢癌慢性应激和耐药最显著相关的基因网络及其组成基因，包括糖酵解途径和 DNA 损伤。本研究建立了尼拉帕利和铂类耐药的体内模型，反映了 OCCS 小鼠重现人类卵巢癌分子机制不同方面的能力，并为克服卵巢癌的双重耐药提供了新的理论依据。
