Tolerance to endoplasmic reticulum stress mediates cisplatin resistance in human ovarian cancer cells by maintaining endoplasmic reticulum and mitochondrial homeostasis

Xu,Ye; Wang,Chunyan; Su,Jing; Xie,Qi; Ma,Liwei; Zeng,Linchuan; Yu,Yang; Liu,Shibing; Li,Songyan; Li,Zhixin; Sun,Liankun

doi:10.3892/or.2015.4283

Tolerance to endoplasmic reticulum stress mediates cisplatin resistance in human ovarian cancer cells by maintaining endoplasmic reticulum and mitochondrial homeostasis

Authors:
- Ye Xu
- Chunyan Wang
- Jing Su
- Qi Xie
- Liwei Ma
- Linchuan Zeng
- Yang Yu
- Shibing Liu
- Songyan Li
- Zhixin Li
- Liankun Sun
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Affiliations: Medical Research Laboratory, Jilin Medical University, Jilin City, Jilin 132013, P.R. China, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China, Department of Histology and Embryology, Jilin Medical University, Jilin City, Jilin 132013, P.R. China
Published online on: September 17, 2015 https://doi.org/10.3892/or.2015.4283
Pages: 3051-3060

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Abstract

The mechanism of cisplatin resistance in ovarian cancer is not fully understood. In the present study, we showed a critical role for endoplasmic reticulum (ER) stress tolerance in mediating cisplatin resistance in human ovarian cancer cells. We found cisplatin to inhibit the proliferation of two ovarian cancer cell lines: cisplatin-sensitive SKOV3 cells and cisplatin‑resistant SKOV3/DDP cells. However, the effect was greater in the cisplatin-sensitive SKOV3 cells. Cisplatin treatment induced ER stress in the SKOV3 cells but not in the SKOV3/DDP cells. Cisplatin-induced Ca2+ flow from the ER into mitochondria caused mitochondrial calcium overload, which amplified proapoptotic signaling in the cisplatin-sensitive SKOV3 cells. ER stress-mediated apoptosis and mitochondrial pathway-dependent apoptosis were induced in the cisplatin-sensitive SKOV3 cells, but not in the cisplatin-resistant SKOV3/DDP cells. Moreover, there were more ER-mitochondria contacts in the cisplatin-treated SKOV3 cells. Collectively, our data indicated that tolerance to cisplatin-induced ER stress inhibits ER stress-mediated apoptosis, prevents an imbalance in ER and mitochondrial calcium homeostasis and maintains cell survival, thus leading to cisplatin resistance in ovarian cancer cells.

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