Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China.
Department of Hematology, Linfen Central Hospital, Linfen, Shanxi 041099, P.R. China.
Oncol Rep. 2024 Sep;52(3). doi: 10.3892/or.2024.8781. Epub 2024 Jul 26.
Ovarian cancer is a gynecological malignant tumor with the highest mortality rate, and chemotherapy resistance seriously affects patient therapeutic outcomes. It has been shown that the high expression of anti‑apoptotic proteins Bcl‑2 and Bcl‑xL is closely related to ovarian cancer chemotherapy resistance. Therefore, reducing Bcl‑2 and Bcl‑xL expression levels may be essential for reversing drug resistance in ovarian cancer. ABT‑737 is a BH3‑only protein mimetic, which can effectively inhibit the expression of the anti‑apoptotic proteins Bcl‑xL and Bcl‑2. Although it has been shown that ABT‑737 can increase the sensitivity of ovarian cancer cells to cisplatin, the specific molecular mechanism remains unclear and requires further investigation. In the present study, the results revealed that ABT‑737 can significantly increase the activation levels of JNK and ASK1 induced by cisplatin in A2780/DDP cells, which are cisplatin‑resistant ovarian cancer cells. Inhibition of the JNK and ASK1 pathway could significantly reduce cisplatin cytotoxicity increased by ABT‑737 in A2780/DDP cells, while inhibiting the ASK1 pathway could reduce JNK activation. In addition, it was further determined that ABT‑737 could increase reactive oxygen species (ROS) levels in A2780/DDP cells induced by cisplatin. Furthermore, the inhibition of ROS could significantly reduce JNK and ASK1 activation and ABT‑737‑mediated increased cisplatin cytotoxicity in A2780/DDP cells. Overall, the current data identified that activation of the ROS‑ASK1‑JNK signaling axis plays an essential role in the ability of ABT‑737 to increase cisplatin sensitivity in A2780/DDP cells. Therefore, upregulation the ROS‑ASK1‑JNK signaling axis is a potentially novel molecular mechanism by which ABT‑737 can enhance cisplatin sensitivity of ovarian cancer cells. In addition, the present research can also provide new therapeutic strategies and new therapeutic targets for patients with cisplatin‑resistant ovarian cancer with high Bcl‑2/Bcl‑xL expression patterns.
卵巢癌是一种妇科恶性肿瘤，死亡率最高，化疗耐药严重影响患者的治疗效果。已有研究表明，抗凋亡蛋白 Bcl-2 和 Bcl-xL 的高表达与卵巢癌化疗耐药密切相关。因此，降低 Bcl-2 和 Bcl-xL 的表达水平可能是逆转卵巢癌耐药的关键。ABT-737 是一种 BH3 结构域蛋白模拟物，可有效抑制抗凋亡蛋白 Bcl-xL 和 Bcl-2 的表达。虽然已有研究表明 ABT-737 可增加卵巢癌细胞对顺铂的敏感性，但具体的分子机制尚不清楚，需要进一步研究。本研究结果表明，ABT-737 可显著增加顺铂诱导的耐药卵巢癌细胞 A2780/DDP 中 JNK 和 ASK1 的激活水平。抑制 JNK 和 ASK1 通路可显著降低 ABT-737 增加 A2780/DDP 细胞中顺铂细胞毒性的作用，而抑制 ASK1 通路可降低 JNK 的激活。此外，进一步确定 ABT-737 可增加顺铂诱导的 A2780/DDP 细胞中活性氧（ROS）的水平。此外，ROS 的抑制可显著降低 JNK 和 ASK1 的激活以及 ABT-737 介导的 A2780/DDP 细胞中顺铂细胞毒性的增加。总之，目前的数据表明，ROS-ASK1-JNK 信号轴的激活在 ABT-737 增加 A2780/DDP 细胞中顺铂敏感性的能力中发挥重要作用。因此，上调 ROS-ASK1-JNK 信号轴是 ABT-737 增强卵巢癌细胞对顺铂敏感性的潜在新分子机制。此外，本研究还可为表达高 Bcl-2/Bcl-xL 模式的顺铂耐药卵巢癌患者提供新的治疗策略和新的治疗靶点。
