Ovarian cancer is the most frequent cause of gynecologic malignancies associated death. Primary or acquired cisplatin resistance is frequently occurred during ovarian cancer therapy. Cancer stem cells (CSC) tend to form minimal residual disease after chemotherapy and are implicated in relapse. The ability of cancer cells to reprogram their metabolism has recently been related with maintenance of CSC and resistance to chemotherapies. The current study found that BAG5 expression was decreased in cisplatin-resistant ovarian cancer cells and clinical tissues. Our data demonstrated that BAG5 knockdown was implicated in metabolic reprogramming and maintenance of cancer stem cell (CSC)-like features of ovarian cancer cells via regulation of Rictor and subsequent mTORC2 signaling pathway. In addition, the current study demonstrated that Bcl6 upregulation was responsible for repression of BAG5 transactivation via recruitment on the BAG5 promoter in cisplatin-resistant ovarian cancer. The current study also demonstrated reverse correlations between BAG5 and Bcl6, BAG5 and Rictor in ovarian serous adenocarcinoma tissues. Collectively, the current study identified the implication of Bcl6/BAG5/Rictor-mTORC2 signaling pathway in metabolic reprograming and maintenance of CSC-like features in cisplatin-resistant ovarian cancer cells. Therefore, further studies on the mechanism underlying regulation of metabolic reprogramming and CSC-like characteristics of cisplatin-resistant ovarian cancer cells may contribute to the establishment of novel therapeutic strategy for cisplatin-resistance.

卵巢癌是妇科恶性肿瘤相关死亡的最常见原因。原发性或获得性顺铂耐药在卵巢癌治疗期间经常发生。癌症干细胞 (CSC) 往往在化疗后形成微小残留病灶，并与复发有关。最近，癌细胞重新编程其代谢的能力与 CSC 的维持和对化疗的抵抗力有关。目前的研究发现，在顺铂耐药的卵巢癌细胞和临床组织中，BAG5的表达降低。我们的数据表明，通过调节 Rictor 和随后的 mTORC2 信号通路，BAG5 敲低与卵巢癌细胞的代谢重编程和维持癌症干细胞 (CSC) 样特征有关。此外，目前的研究表明，在顺铂耐药的卵巢癌中，Bcl6 上调是通过招募 BAG5 启动子来抑制 BAG5 反式激活的原因。目前的研究还证明了卵巢浆液性腺癌组织中 BAG5 和 Bcl6、BAG5 和 Rictor 之间的反向相关性。总的来说，目前的研究确定了 Bcl6/BAG5/Rictor-mTORC2 信号通路在顺铂耐药卵巢癌细胞中代谢重编程和维持 CSC 样特征中的意义。因此，进一步研究顺铂耐药卵巢癌细胞代谢重编程的调控机制和CSC样特征，可能有助于建立新的顺铂耐药治疗策略。