Melatonin increases human cervical cancer HeLa cells apoptosis induced by cisplatin via inhibition of JNK/Parkin/mitophagy axis

Abstract

Considering that chemotherapy resistance is vital to the progression of cervical carcinoma, emerging researchers are focused on developing anti-tumor drugs to assist the treatment efficiency of chemotherapy. Melatonin has anti-tumor activity via several mechanisms including its anti-proliferative and pro-apoptotic effects as well as its potent pro-oxidant action in tumor cells. Therefore, melatonin may be useful for the treatment of tumors in association with chemotherapy drugs. Here, we studied the effect and mechanism of melatonin on HeLa cells apoptosis under cisplatin (CIS) treatment, particularly focusing on the caspase-9-related apoptosis pathway and mitophagy-mediated anti-apoptotic mechanism. The result indicated that co-stimulation of HeLa cells with CIS in the presence of melatonin further increased cellular apoptosis. Furthermore, concomitant treatments with melatonin and CIS significantly enhanced the mitochondrial structure and function damage, substantially augmented the caspase-9-dependent mitochondrial apoptosis with evidenced by lower mitochondria membrane potential, higher mitochondria ROS, and more pro-apoptotic proteins compared to the treatment with CIS alone. Mechanistically, melatonin inactivated mitophagy via blockade of JNK/Parkin, leading to the inhibition of anti-apoptotic mitophagy. The mitophagy had the ability to clear and remove damaged mitochondria, impairing CIS-mediated mitochondrial apoptosis. Activation of JNK/Parkin could alleviate the lethal effect of melatonin on HeLa cells. In summary, this study confirmed that melatonin sensitizes human cervical cancer HeLa cells to CIS-induced apoptosis through inhibition of JNK/Parkin/mitophagy pathways.