Nuclear translocation and activation of YAP by hypoxia contributes to the chemoresistance of SN38 in hepatocellular carcinoma cells
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Xiao-Yang Dai1,2,*, Lin-Han Zhuang1,*, Dan-Dan Wang1,*, Tian-Yi Zhou1, Lin-Lin Chang1, Ren-Hua Gai2, Di-Feng Zhu2, Bo Yang1, Hong Zhu1, Qiao-Jun He1
1Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
2Center for Drug Safety Evaluation and Research of Zhejiang University, Hangzhou 310058, China
*These authors contributed equally to this work
Hong Zhu, e-mail: [email protected]
Qiao-Jun He, e-mail: [email protected]
Keywords: hepatocellular carcinoma, SN38, hypoxia, resistance, yes-associated protein (YAP)
Received: June 23, 2015 Accepted: December 29, 2015 Published: January 12, 2016
Although hypoxia is a prominent feature contributing to the therapeutic resistance of hepatocellular carcinoma cells (HCC) against chemotherapeutic agents, including the Topoisomerase I inhibitor SN38, the underlying mechanism is not fully understood and its understanding remains a major clinical challenge. In the present study, we found that hypoxia-induced nuclear translocation and accumulation of YAP acted as a survival input to promote resistance to SN38 in HCC. The induction of YAP by hypoxia was not mediated by HIF-1α because manipulating the abundance of HIF-1α with CoCl2, exogenous expression, and RNA interference had no effect on the phosphorylation or total levels of YAP. The mevalonate-HMG-CoA reductase (HMGCR) pathway may modulate the YAP activation under hypoxia. Combined YAP inhibition using either siRNA or the HMGCR inhibitor statins together with SN38 treatment produced improved anti-cancer effects in HCC cells. The increased anti-cancer effect of the combined treatment with statins and irinotecan (the prodrug of SN-38) was further validated in a human HepG2 xenograft model of HCC in nude mice. Taken together, our findings identify YAP as a novel mediator of hypoxic-resistance to SN38. These results suggest that the administration of SN28 together with the suppression of YAP using statins is a promising strategy for enhancing the treatment response in HCC patients, particularly in advanced stage HCC cases presenting hypoxic resistance.
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