TRP14 promotes resistance to cisplatin by inducing autophagy in ovarian cancer

Abstract

Cisplatin is a common chemotherapeutic agent against ovarian cancer; however, drug resistance is a major limiting factor for its use in clinical treatment. The underlying mechanisms of cisplatin resistance in ovarian cancer have not yet been fully elucidated. Thus, this study aimed to elucidate some of the mechanisms responsible for resistance to cisplatin in ovarian cancer. The results demonstrated that the cisplatin-resistant human ovarian cancer cell lines, SKOV3/DDP and A2780/DDP, exhibited higher autophagy levels than the control ovarian cancer cell lines, SKOV3 and A2780. Moreover, autophagy inhibition by 3-methyladenine or shRNA against autophagy-related gene (ATG)5 potentiated the cytotoxicity induced by cisplatin, whereas autophagy induction by rapamycin (Rapa) increased cell survival. Exposure to cisplatin induced an upregulation in the expression of thioredoxin-related protein of 14 kDa (TRP14). Furthermore, TRP14 knockdown or overexpression decreased or increased the autophagy response and cisplatin resistance, and this effect was reversed by treatment with Rapa or ATG5 knockdown. The findings of this study also suggested that TRP14 induced autophagy and chemoresistance via the 5′AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/p70S6K signaling pathway. Importantly, the data from a tissue array revealed a positive association between TRP14 and Beclin1 in human ovarian cancer and marginal tissues. These findings have identified, for the first time, to the best of our knowledge, that TRP14 induces autophagy and consequently cisplatin resistance in ovarian cancer cells via the AMPK/mTOR/p70S6K signaling pathway. This in turn renders TRP14 as a potential predictor or target in ovarian cancer therapy.