ABT-737 reverses cisplatin resistance through ROS-ASK1-JNK MAPK signaling pathway and Ca2+ signaling in human ovarian cancer cells

Abstract

Abstract ABT-737, is a BH3-only protein mimetic, which can effectively inhibit the anti-apoptotic proteins Bcl-xL and Bcl-2. A large number of studies have shown that ABT-737 can induce a variety of tumor cell apoptosis, and also enhance cisplatin induced tumor cell apoptosis. However, the mechanism of ABT-737 enhances the sensitivity of ovarian cancer cells to cisplatin is still unclear and needs further study. Our results showed that ABT-737 can significantly increase the sensitivity of A2780/DDP cells to cisplatin. We detected that ABT-737 could significantly increase the activation levels of JNK and ASK1 in A2780/DDP cells induced by cisplatin. Inhibition of JNK and ASK1 pathway could significantly reduce cisplatin sensitivity increased by ABT-737 in A2780/DDP cells, and inhibition of ASK1 pathway could significantly reduce the activation level of JNK. We further detected that ABT-737 could ovbiously increase the level of reactive oxygen species (ROS) in A2780/DDP cells induced by cisplatin, and the inhibition of ROS could significantly reduce the activation levels of JNK and ASK1, as well as could significantly reduce cisplatin sensitivity increased by ABT-737 in A2780/DDP cells. Moreover, calcium chelators can significantly reduce cisplatin sensitivity increased by ABT-737 in A2780/DDP cells, the result is consistent with the current reports. These results suggested that ROS-ASK1-JNK signaling axis and calcium signaling play an important role in ABT-737 reversing cisplatin resistance in ovarian cancer. This might be a novel molecular mechanism of ABT-737 enhances the sensitivity of ovarian cancer cells to cisplatin through regulating ROS-ASK1-JNK signaling axis.