PGC1α promotes cisplatin resistance in human ovarian carcinoma cells through upregulation of mitochondrial biogenesis

Shen,Luyan; Sun,Boyang; Sheng,Jiyao; Yu,Sihang; Li,Yanqing; Xu,Huadan; Su,Jing; Sun,Liankun

doi:10.3892/ijo.2018.4401

PGC1α promotes cisplatin resistance in human ovarian carcinoma cells through upregulation of mitochondrial biogenesis

Authors:
- Luyan Shen
- Boyang Sun
- Jiyao Sheng
- Sihang Yu
- Yanqing Li
- Huadan Xu
- Jing Su
- Liankun Sun
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Affiliations: Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China, Department of Biochemistry and Molecular Biology, Basic College of Medicine, Yanbian University, Yanbian Korean Autonomous Prefecture, Jilin 133002, P.R. China, Department of Hepatobiliary and Pancreas Surgery, Second Hospital, Jilin University, Changchun, Jilin 130041, P.R. China
Published online on: May 9, 2018 https://doi.org/10.3892/ijo.2018.4401
Pages: 404-416

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Abstract

The induction of lesions in nuclear and mitochondrial DNA by cisplatin is only a small component of its cytostatic/cytotoxic activity. The signaling pathway network in the nucleus and cytoplasm may contribute to chemotherapeutic resistance. Peroxisome proliferator-activated receptor-coactivator 1α (PGC1α)-mediated mitochondrial biogenesis regulates mitochondrial structural and the functional adaptive response against chemotherapeutic stress, and may be a therapeutic target. However, this regulatory network is complex and depends upon tumor types and environments, which require further investigation. Our previous study found that cisplatin-resistant ovarian epithelial carcinoma was more dependent on mitochondrial aerobic oxidation to support their growth, suggesting the association between mitochondrial function and chemotherapeutic resistance. In the present study, it was demonstrated that the expression of PGC1α and level of mitochondrial biogenesis were higher in cisplatin-resistant SKOV3/DDP cells compared with cisplatin-sensitive SKOV3 cells. Furthermore, SKOV3/DDP cells upregulated the expression of PGC1α and maintained mitochondrial structural and functional integrity through mitochondrial biogenesis under cisplatin stress. Inhibiting the expression of PGC1α using short hairpin RNA led to the downregulation of mitochondrial biogenesis and high levels of apoptosis in the SKOV3/DDP cells, and cisplatin resistance was reversed in the PGC1α-deficient SKOV3/DDP cells. Collectively, the present study provided evidence that cisplatin stimulated the expression of PGC1α and the upregulation of mitochondrial biogenesis through PGC1α, promoting cell viability and inhibiting apoptosis in response to cisplatin treatment, thus triggering cisplatin resistance in ovarian cancer cells.

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