ABT‑737 increases cisplatin sensitivity through the ROS‑ASK1‑JNK MAPK signaling axis in human ovarian cancer cisplatin‑resistant A2780/DDP cells

Abstract

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.