Epoxycytochalasin H: An Endophytic Phomopsis Compound Induces Apoptosis in A2780 Cells Through Mitochondrial Damage and Endoplasmic Reticulum Stress.

ABSTRACT

BACKGROUND: Natural compounds extracted from plants have been reported to have antitumor activity. A fungal metabolite from Phomopsis, identified as epoxycytochalasin H and isolated from the flowering plant Polygonatum sibiricum, was found to have significant antitumor activity. In this study, we report the antitumor effects and mechanism of action of epoxycytochalasin H in the ovarian cancer cell line A2780. Our data suggest that epoxycytochalasin H markedly reduces cell proliferation and induces apoptosis in ovarian cancer cells. MATERIALS AND METHODS: The viability, apoptosis and colony formation of A2780 cells, treated with epoxycytochalasin H, were detected by MTT assay, nuclear staining, flow cytometry, and clone formation assay. MitoROS and mitochondrial membrane potentials were detected by MitoSOX staining and flow cytometry. The expression of proteins associated with apoptosis, autophagy, and endoplasmic reticulum stress, in A2780 cells treated with epoxycytochalasin H, was detected by Western blot. Effects of mitophagy were detected in Parkin-overexpressing 293T cells. RESULTS: Our data suggested that epoxycytochalasin H could strongly reduce cell proliferation and induce apoptosis in ovarian cancer cell line A2780. Epoxycytochalasin H induced apoptosis through mitochondrial injury, mitophagy, and endoplasmic reticulum stress. Specifically, epoxycytochalasin H increased ROS level in cells, and in mitochondria, it decreased mitochondrial membrane potential, caused mitochondrial injury, activated macroautophagy and mitophagy, and subsequently induced apoptosis via the mitochondrial pathway. Additionally, it was discovered that epoxycytochalasin H could induce apoptosis more significantly in 293T cells overexpressing Parkin than in the parental cells. Thus, the mitophagy activated by epoxycytochalasin H could promote apoptosis. In addition, epoxycytochalasin H mediated endoplasmic reticulum stress-related apoptosis. CONCLUSION: Epoxycytochalasin H could promote apoptosis of human ovarian cancer A2780 cells by activating mitochondrial and endoplasmic reticulum stress-related apoptotic pathways.