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YAP induces cisplatin resistance through activation of autophagy in human ovarian carcinoma cells

Authors Xiao L, Shi X, Zhang Y, Zhu Y, Zhu L, Tian W, Zhu B, Wei Z

Received 19 December 2015

Accepted for publication 25 January 2016

Published 16 March 2016 Volume 2016:9 Pages 1105—1114

DOI https://doi.org/10.2147/OTT.S102837

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Lucy Goodman

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Geoffrey Pietersz


Lan Xiao,1,* Xiao-Yan Shi,2,* Ying Zhang,1 Ying Zhu,1 Lin Zhu,3 Wang Tian,1 Bing-Kun Zhu,1 Zhao-Lian Wei1

1Department of Obstetrics and Gynecology, First Affiliated Hospital, Anhui Medical University, Hefei, 2Key Laboratory for Molecular Diagnosis of Hubei Province, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 3Obstetrics and Gynecology Hospital of Fudan University (Shanghai Red House Obstetrics and Gynecology Hospital), Shanghai, People’s Republic of China

*These authors contributed equally to this work

Objective: To identify the role of YAP in cisplatin resistance in human ovarian cancer cells and in the regulation of autophagy in these cancer cells.
Materials and methods: The cisplatin-sensitive OV2008 parental cell line and its cisplatin-resistant variant C13K were cultured. RNA interference was used to knock down the YAP gene. Accumulation of GFP-LC3 puncta was performed by fluorescence microscopy. The formation of autophagosomes was observed by transmission electron microscopy. Drug sensitivity was examined using CCK-8 assay, while apoptosis, the level of intracellular rhodamine 123 and lysosomal acidification were analyzed by fluorescence-activated cell sorting. Acid phosphatase activity was measured using an acid phosphatase-assay kit. Real-time polymerase chain reaction, Western blotting, and immunofluorescence detection were used to detect the protein and messenger RNA expression of YAP, YAP target genes, CCND1, cleaved PARP, and caspase 3, Atg-3 and -5, and the LC3B protein.
Results: YAP signaling may regulate cisplatin resistance in ovarian cancer cells by augmenting cellular autophagic flux. After knockdown of YAP-sensitized C13K cells to cisplatin by inducing a decrease in autophagy, YAP led to an increase in autophagy via enhancement of autolysosome degradation.
Conclusion: YAP-mediated autophagy may play a protective role in cisplatin-resistant human ovarian cancer cells. Therefore, YAP-mediated autophagy should be explored as a new target for enhancing the efficacy of cisplatin against ovarian cancer and other types of malignancies.

Keywords: YAP protein, autophagy, cisplatin resistance, ovarian carcinoma

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