Hypoxia was a prominent feature of hepatocellular carcinoma cells （HCC）, contributing to therapeutic resistance towards a variety chemotherapeutic agents including Topoisomerase I inhibitor SN38, with mechanism not...Hypoxia was a prominent feature of hepatocellular carcinoma cells （HCC）, contributing to therapeutic resistance towards a variety chemotherapeutic agents including Topoisomerase I inhibitor SN38, with mechanism not yet fully understood, thus remaining a major clinical challenge. Herein, we present evidences that the hypoxia-in- duced nuclear translocation and accumulation of Yes-associated protein （YAP） acts as a survival input to promote hypoxic-resistance to SN38 in HCC. YAP induction by hypoxia was not mediated by HIF-lα, since the manipula- tion of HIF-1α either by COC12, exogenous expression nor siRNA of HIF-1α imposed any effect on the phosphoryla- tion or total level of YAP. Instead, mevalonate-HMG-CoA reductase （HMGCR） pathway may modulate the YAP pathway under hypoxia. Combined YAP inhibition by either siRNA or HMGCR inhibitor statins with SN38 achieved improved anti-cancer activities in HCC cells. Moreover, the increased anti-cancer efficacy of statins combined with irinotecan （the prodrug of SN-38 ） was further validated in a human HCC HepG2 xenografl model in nude mice. Taken together, our findings identify YAP as a novel mechanism of hypoxic-resistance to SN38. These results un- veil the combined suppression of YAP （ for instance , statins） and SN38 as a potential promising strategy to enhance treatment response of HCC patients, particularly those with advanced stage suffering from hypoxic resistance.展开更多
文摘Hypoxia was a prominent feature of hepatocellular carcinoma cells （HCC）, contributing to therapeutic resistance towards a variety chemotherapeutic agents including Topoisomerase I inhibitor SN38, with mechanism not yet fully understood, thus remaining a major clinical challenge. Herein, we present evidences that the hypoxia-in- duced nuclear translocation and accumulation of Yes-associated protein （YAP） acts as a survival input to promote hypoxic-resistance to SN38 in HCC. YAP induction by hypoxia was not mediated by HIF-lα, since the manipula- tion of HIF-1α either by COC12, exogenous expression nor siRNA of HIF-1α imposed any effect on the phosphoryla- tion or total level of YAP. Instead, mevalonate-HMG-CoA reductase （HMGCR） pathway may modulate the YAP pathway under hypoxia. Combined YAP inhibition by either siRNA or HMGCR inhibitor statins with SN38 achieved improved anti-cancer activities in HCC cells. Moreover, the increased anti-cancer efficacy of statins combined with irinotecan （the prodrug of SN-38 ） was further validated in a human HCC HepG2 xenografl model in nude mice. Taken together, our findings identify YAP as a novel mechanism of hypoxic-resistance to SN38. These results un- veil the combined suppression of YAP （ for instance , statins） and SN38 as a potential promising strategy to enhance treatment response of HCC patients, particularly those with advanced stage suffering from hypoxic resistance.
