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

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.

Organoruthenium Complexes with Benzo-Fused Pyrithiones Overcome Platinum Resistance in Ovarian Cancer Cells

“…In combination, both influx and efflux pathways can contribute to drug resistance [63]. For example, cisplatin-resistant A2780Cis cells exhibit downregulation of a copper uptake transporter protein (CTR1) and upregulation of efflux transporters multi-drug resistance protein 2 (MRP-2), ATPase copper transporting α (ATP7A), and ATPase copper transporting β [65].…”

Inhibition of ubiquitin‑specific protease�14 promotes connexin�32 internalization and counteracts cisplatin cytotoxicity in human ovarian cancer cells

“…Kawasaki et al and Li et al reported that cytoplasmic accumulation of Cx32 expanded the cancer stem cell population and enhanced the motility and metastatic ability of human hepatoma cells (9,10). Studies performed by our team demonstrated that upregulated Cx32 in cervical ovarian and liver cancer cells was mainly localized in the cytoplasm and produced anti-apoptotic and pro-tumor effects in a GJ-independent manner (11)(12)(13)(14). Nevertheless, the mechanism of the upregulation and internalization of Cx32 remains unknown.…”

Low Expression of SLC7A11 Confers Drug Resistance and Worse Survival in Ovarian Cancer via Inhibition of Cell Autophagy as a Competing Endogenous RNA

“…As shown in Figure 8 , the PPI network indicated that SLC7A11 directly interacted with 16 proteins, and indirectly interacted with the remaining 15 proteins. All the 16 proteins have been reported to be implicated in the modulation of drug resistance in OC, namely ABCC1 ( 48 ), ABCC2 ( 49 ), ABCB1 ( 50 ), CD44 ( 51 ), ALDH1A1 ( 52 ), ABCG2 ( 53 ), PROM1 ( 54 ), CDKN1A ( 55 ), CDH1 ( 56 ), EGFR ( 57 ), BRCA1 ( 58 ), BRCA2 ( 58 ), BCL2L1 ( 59 ), MDM4 ( 60 ), MTOR ( 61 ), and BRAF ( 62 ); and among the 15 proteins, nine of them were reported to be implicated in drug resistance, which were ERCC1 ( 63 ), MVP ( 64 ), ERBB2 ( 65 ) TP53 ( 66 ), PARP1 ( 58 ), MSH3 ( 67 ), BCL2 ( 68 ), CASP3 ( 69 ), and PTEN ( 70 ). The results above indicated that among the 31 proteins, SLC7A11 interacted with 25 OC drug resistance-related proteins, providing strong PPI network evidence to support the relationship between SLC7A11 and drug resistance in OC.…”