Anti-neoplastic effect of mangiferin on human ovarian adenocarcinoma OVCAR8 cells via the regulation of YAP.

Abstract

Ovarian cancer is the most malignant gynecologic neoplasm in women and has the worst prognosis of all cancer types in women based on the 5-year survival rates. A previous study indicated that mangiferin exerts an anti-neoplastic effect on human ovarian cancer cells by targeting Notch3. Additionally, it has been demonstrated that Notch signaling is a functionally important downstream effector of Yes-associated protein (YAP), therefore it was hypothesized that YAP may be involved in the antitumor effect of mangiferin. The present study aimed to further reveal the mangiferin-mediated inhibitory effect on ovarian cancer and investigate the molecular anticancer mechanism of mangiferin. Based on the in vitro data, accompanied with the significantly reduced cell proliferation of mangiferin-treated cells compared with mangiferin-treated YAP-overexpressed cells (P<0.05), YAP expression was identified to be substantially downregulated by mangiferin. In contrast, observations of the cell morphology and apoptotic percentages revealed that the antitumor effect of mangiferin may be reversed by YAP overexpression. Furthermore, decreased levels of migration and invasion were observed in mangiferin-treated cells, which may also be abrogated by YAP overexpression. Thus, these data further demonstrated that mangiferin inhibits metastasis by regulating YAP. Additionally, due to the frequent chemoresistance observed in cisplatin-based chemotherapy, the present study evaluated the cisplatin resistance in OVCAR8 cells and elucidated that mangiferin may sensitize the tumor cells to cisplatin; and this improved sensitization was also abolished by YAP overexpression. These results collectively indicated that YAP was not only closely associated with the anticancer effect of mangiferin, but also mediated drug resistance in tumor. Furthermore, the downregulation of downstream TEA domain transcription factor 4 expression was observed in the mangiferin-treated cells, further validating the inhibitory effect of mangiferin on YAP. In addition, OVCAR8 cell xenograft models revealed that through increasing the sensitivity of a tumor to cisplatin, mangiferin inhibited the growth of a tumor and increased the survival time of tumor xenograft mice. Based on these results, it was concluded that mangiferin may inhibit tumor cell growth and enhance cisplatin-sensitivity in OVCAR8 cells via the regulation of the YAP pathway. Altogether, by targeting YAP and enhancing the response to cisplatin treatment, mangiferin potentially functioned as a novel therapeutic agent in the treatment of ovarian cancer.