Nobiletin Triggers Reactive Oxygen Species-Mediated Pyroptosis through Regulating Autophagy in Ovarian Cancer Cells.

ABSTRACT

Ovarian cancer is one of the most serious female malignancies worldwide. Despite intensive efforts being made to overcome ovarian cancer, there still remain limited optional treatments for this disease. Nobiletin, a prospective food-derived phytochemical extracted from citrus fruits, has recently been reported to suppress ovarian cancer cells, but the role of pyroptosis in ovarian carcinoma with nobiletin still remains unknown. In this study, we aim to explore the effect of nobiletin on ovarian carcinoma and further expound the underlying mechanisms of nobiletin-induced ovarian cancer cell death. Our results showed that nobiletin could significantly inhibit cell proliferation, induce DNA damage, and also lead to apoptosis by increasing the cleaved poly (ADP-ribose) polymerase (PARP) level of human ovarian cancer cells (HOCCs) in a dose-dependent manner. Moreover, we revealed that nobiletin decreased mitochondrial membrane potential and induced reactive oxygen species (ROS) generation and autophagy of HOCCs, contributing to gasdermin D-/gasdermin E-mediated pyroptosis. Taken together, nobiletin as a functional food ingredient represents a promising new anti-ovarian cancer candidate that could induce apoptosis and trigger ROS-mediated pyroptosis through regulating autophagy in ovarian cancer cells.