miR214-regulated p53-NOX4/p66shc pathway plays a crucial role in the protective effect of Ginkgolide B against cisplatin-induced cytotoxicity in HEI-OC1 cells
Abstract
The chemotherapeutic agent, cisplatin, is widely used for the treatment of several neoplastic diseases. The concomitant cytotoxicity in cochlear cells severely limits the maximum dose of cisplatin. Our previous study has shown that Ginkgolide B (GB) could protect against cisplatin-induced ototoxicity. In the present study, we aimed to elucidate the probable mechanism underlying GB-mediated protective effects against cisplatin-induced cytotoxicity. The results showed that, in HEI-OC1 auditory cells, both NOX4 and p66(shc) expression was increased by cisplatin. GB significantly reduced NOX4 and p66(shc) expression and superoxide generation. Over-expression of NOX4 or p66(shc) suppressed the inhibitory effects of GB on superoxide generation and the protective effects of GB on loss of cell viability and apoptosis associated with cisplatin. Moreover, p53 expression was increased by cisplatin. GB significantly decreased p53 expression and p53-binding of the promoters of NOX4 and p66(shc). Over-expression of p53 suppressed the inhibitory effects of GB on NOX4 and p66(shc) expression and superoxide generation and the protective effects of GB on loss of cell viability and apoptosis associated with cisplatin. Furthermore, miR214 expressi...Continue Reading
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