Cx32 mediates cisplatin resistance in human ovarian cancer cells by affecting drug efflux transporter expression and activating the EGFR‑Akt pathway

Zhang,Yu; Tao,Liang; Fan,Li‑Xia; Huang,Kun; Luo,Hui‑Min; Ge,Hui; Wang,Xiyan; Wang,Qin

doi:10.3892/mmr.2019.9876

Cx32 mediates cisplatin resistance in human ovarian cancer cells by affecting drug efflux transporter expression and activating the EGFR‑Akt pathway

Authors:
- Yu Zhang
- Liang Tao
- Li‑Xia Fan
- Kun Huang
- Hui‑Min Luo
- Hui Ge
- Xiyan Wang
- Qin Wang
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Affiliations: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat‑Sen University, Guangzhou, Guangdong 510080, P.R. China, Tumor Research Institute, Xinjiang Medical University Affiliated Tumour Hospital, Urumqi, Xinjiang Uygur Autonomous Region 830000, P.R. China
Published online on: January 17, 2019 https://doi.org/10.3892/mmr.2019.9876
Pages: 2287-2296

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Abstract

Our previous study demonstrated that connexin 32 (Cx32) was upregulated and redistributed to the cytoplasm in A2780 human ovarian cancer cells with acquired resistance to cisplatin; this increased Cx32 feedback promoted cisplatin resistance. To further investigate the mechanism underlying Cx32‑mediated cisplatin resistance, alterations in drug transporters, the DNA repair system and the anti‑apoptotic signalling pathway were investigated by overexpressing or knocking down Cx32 in parental cells (A2780); cisplatin‑resistant human ovarian cancer cells (A2780/CDDP) were also acquired. Upregulation of efflux transporters [multi‑drug resistance protein 2 (MRP‑2), ATPase copper transporting α (ATP7A) and ATPase copper transporting β] and downregulation of the influx transporter copper uptake protein 1 mediated cisplatin resistance in A2780/CDDP cells. A2780/CDDP cells also exhibited increased expression of the DNA repair enzyme excision repair cross‑complementation group 1 (ERCC1) and activation of the epidermal growth factor receptor (EGFR) signalling pathway. Small interfering RNA‑mediated knockdown of Cx32 in A2780/CDDP cells decreased the expression of efflux transporters (MRP‑2 and ATP7A). Knockdown of Cx32 in A2780/CDDP cells also decreased the expression of ERCC1, inhibited the activation of the EGFR signalling pathway and enhanced the cytotoxicity of cisplatin. When Cx32 was overexpressed in A2780 cells, an opposite effect on the expression of efflux transporters (MRP‑2 and ATP7A) and the activation of the EGFR signalling pathway was observed, which resulted in insensitivity to cisplatin‑induced apoptosis. Thus, Cx32 expression may induce cisplatin resistance by modulating drug efflux transporter expression and activating the EGFR‑protein kinase B signalling pathway in ovarian cancer cells.

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