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The E3 ubiquitin protein ligase MDM2 dictates ATRA-induced osteoblastic differentiation of osteosarcoma cells by

中国药理学通报 2015年第B11期31卷 64-65页

作者： ZHOUQian SHAOXue-jing zhejiangprovincekeylaboratoryofanti-cancerdrugresearch CollegeofPharmaceuticalSciencesZhejiangUniversityHangzhou310058

Aim Retinoic acid receptor alpha （RARα） plays a critical role in the differentiation process of osteo- sarcoma cells induced by all-trans retinoic acid （ATRA）. However, degradation of RARoL through ubiquitin pro- teasome pathway weakens the differentiation efficiency of osteosarcoma cells. Therefore, it is necessary to explore the regulatory mechanisms involved in RARoL degradation. Methods U2OS cells were mainly used as our research models. （1） Protein levels were detected by Western blot; （2） The interactions between MDM2 and RARalpha were determined by immunofluorescence and immunoprecipitation; （3） Related proteins and genes were investiga- ted via transfection; （4） The expression levels of MDM2 and OPN in patient biopsies were detected by immunohis- tochemistry; （5） Alkaline phosphatase activity was assessed by colorimetric assays using the BCIP/NBT Alkaline Phosphatase Color Development kit. Results In this report, it demonstrated that interaction with MDM2 leaded to strong stimulation of RARoL polyubiquitination and degradation by proteasomes. MDM2 appeared to function as an ubiquitin E3 ligase in this process, since the MDM2 RING domain mutant inhibited the ubiquitination of RARoL. Furthermore, MDM2 was capable of stimulating RARoL polyubiquitination under cell-free conditions. Moreover, it also provided evidence that silencing or inhibiting MDM2 promotes the differentiation of U2OS cells as induced by ATRA. Conclusions MDM2 serves as an E3 ubiquitin ligase to regulate the degradation of RARoL and becomes a novel therapeutic target for ATRA-based differentiation therapeutic approaches in osteosarcoma.

关键词： osteosarcoma RARα degradation MDM2 all-trans retinoic acid differentiation

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Nuclear Translocation and Activation of YAP by Hypoxia Contributes to Chemoresistance of SN38 in Hepatocellular Carcinoma Cells

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中国药理学通报 2015年第B11期31卷 238-238页

作者： WANGDan-dan ZHOUTian-yi CHANGLin-lin ZHUHong HEQiao-jun YANGBo zhejiangprovincekeylaboratoryofanti-cancerdrugresearch CollegeofPharmaceuticalSciencesZhejiangUniversityHangzhou310058

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.

关键词： Hepatocellular Carcinoma SN38 Hypoxia resistance Yes-associated protein (YAP) statins

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