TRP14 promotes resistance to cisplatin by inducing autophagy in ovarian cancer

Tan,Wen‑Xi; Xu,Tian‑Min; Zhou,Zi‑Long; Lv,Xue‑Jiao; Liu,Jian; Zhang,Wen‑Jing; Cui,Man‑Hua

doi:10.3892/or.2019.7258

TRP14 promotes resistance to cisplatin by inducing autophagy in ovarian cancer

Authors:
- Wen‑Xi Tan
- Tian‑Min Xu
- Zi‑Long Zhou
- Xue‑Jiao Lv
- Jian Liu
- Wen‑Jing Zhang
- Man‑Hua Cui
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Affiliations: Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China, National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, Jilin 130024, P.R. China, Department of Respiratory Medicine, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China, Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
Published online on: August 2, 2019 https://doi.org/10.3892/or.2019.7258
Pages: 1343-1354
Copyright: © Tan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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.

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