Melatonin synergistically enhances docetaxel induced endoplasmic reticulum stress to promote apoptosis by suppressing NF-κB activation in cervical cancer.

Abstract

Cervical cancer is the fourth most common malignancy in women globally. Although chemotherapy significantly improves the survival of cervical cancer patients, the development of drug resistance is inevitable. In the present study, our study showed that melatonin suppressed the proliferation, cell survival, colony formation, and the ability of adhering to fibronectin in cervical cancer cells. Our data suggested that docetaxel insensitivity was caused by NF-κB pathway activation, and followed by reducing endoplasmic reticulum stress and apoptosis. We showed that melatonin functioned as an oncostatic agent via inhibition of NF-κB signaling in cervical cancer cells. Interestingly, melatonin not only reduced the basal and inducible NF-κB pathway activation, but also prevented docetaxel induced NF-κB pathway activation by stabilizing IκBα protein. Importantly, inhibition of NF-κB pathway activation by melatonin abrogated the protective effect of NF-κB activation on docetaxel provoked endoplasmic reticulum stress, and further enhanced endoplasmic reticulum stress and apoptosis to produce synergistic oncostatic effects in cervical cancer cells. In summary, we revealed that melatonin was a novel agent to enhance docetaxel sensitivity by abolishing NF-κB activation and aggravating endoplasmic reticulum stress. Our results might provide a rationale for the clinical application of melatonin to overcome docetaxel resistance in cervical cancer patients.