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 (ADPribose) 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.

The Role of Citrus Nobiletin on Oxidative Stress Levels and Superoxide Dismutase Activities in Metastatic Castration-Resistant Prostate Cancer

“…In addition, researchers reported that nobiletin impeded cell proliferation both depending on the dose and duration and prevented cell cycle progression in G1 (Morley et al, 2007). Nobiletin can induce DNA damage that contributes to apoptosis by regulating polymerase activity in cancer cells (Zhang et al, 2020). It has been suggested that NOB may be a pathway that triggers pyroptosis associated with apoptosis by inducing IL-1β expression (He et al, 2015).…”

Pyroptosis, a New Breakthrough in Cancer Treatment

“…Zhang et al found that nobiletin could reduce the mitochondrial membrane potential, induce ROS generation, and play a role in GSDMD/GSDME-mediated pyroptosis in HOCC (human ovarian cancer cells). In summary, nobiletin may become a new anti-ovarian cancer drug, which can trigger apoptosis and induce pyroptosis by regulating the autophagy of ovarian cancer cells (132).…”

The role of TRIM family proteins in autophagy, pyroptosis, and diabetes mellitus

“…), the hematopoietic interferon‐inducible nuclear protein with 200 amino acids (HIN200) family member AIM2, and the TRIM family member Pyrin/TRIM20 (Van Opdenbosch & Lamkanfi, 2019). A large number of stimuli can activate inflammasomes, like plasma membrane damage in infection disorders and ROS trigger activation of NLRP3, mediating GSDMD cleavage, and pyroptotic cell death (Beckwith et al, 2020; Liu et al, 2019; Xue et al, 2019; R. Zhang, Chen, et al, 2020; the pyroptotic process is shown in Figure 4).…”