Non-junctional Cx32 mediates anti-apoptotic and pro-tumor effects via epidermal growth factor receptor in human cervical cancer cells / 中国药理学与毒理学杂志

ABSTRACT

ABSTRACTOBJECTIVE To investigate the role of connexin proteins (Cx), which form gap junctions (GJ), in progression and chemotherapeutic sensitivity of cervical cancer (CaCx). METHODS We analyze the expression of Cx26, Cx30, Cx32 and Cx43 in human specimens consisting of Normal cervix (n=78), CaCx FIGO stage Ⅰ (n=148), CaCx FIGO stage Ⅱ (n=165). InCaCx cell lines, Hela- Cx32 (induced expression by doxycycline), C- 33A (endogenously express Cx32) and siHa (transiently transfected plasmid with Cx32), we detected the role of Cx32 against tostreptonigrin/cisplatin-induced apopotosisin presence or absence of functional GJ through using GJ inhibitors or low density cultural.Furtherly, we observed the relativity of Cx32 and EGFR expression in human specimens. Also, we detected the role of EGFR signaling pathway in the process of Cx32 anti-apoptosis through suppressed EGFR expression by inhibitors or siRNA sequences in cell lines. RESULTS We firstly demonstrated the expression of Cx32 was highly upregulated and accumulated in cytoplasm in the CaCx specimens, and the degree of upregulation correlated with advanced FIGO stages. Thus,in three human cervical cell lines, Cx32 was shown to suppress apoptosis when GJ formation is inhibited. No matter in cases of CaCx or cell lines, Cx32 expression was highly correlated with expression of EGFR and the EGFR pathway is an essential component of the Cx32-induced anti-apoptotic effect. CONCLUSION Cx32, traditionally tumor suppressive protein, was shown to be tumor protective against chemotherapy through EGFR pathway in a GJ-independent way.