title: Inactivation of hypoxia-induced YAP by statins overcomes hypoxic resistance tosorafenib in hepatocellular carcinoma cells.
abstract: Sorafenib is a multikinase inhibitor used as a first-line treatment for advanced hepatocellular carcinoma (HCC), but it has shown modest to low response rates. The characteristic tumour hypoxia of advanced HCC maybe a major factor underlying hypoxia-mediated treatment failure. Thus, it is urgent to elucidate the mechanisms of hypoxia-mediated sorafenib resistance in HCC. In this study, we found that hypoxia induced the nuclear translocation of Yes associate-Protein (YAP) and the subsequent transactivation of target genes that promote cell survival and escape apoptosis, thereby leading to sorafenib resistance. Statins, the inhibitors of hydroxymethylglutaryl-CoA reductase, could ameliorate hypoxia-induced nuclear translocation of YAP and suppress mRNA levels of YAP target genes both in vivo and in vitro. Combined treatment of statins with sorafenib greatly rescued the loss of anti-proliferative effects of sorafenib under hypoxia and improved the inhibitory effects on HepG2 xenograft tumour growth, accompanied by enhanced apoptosis as evidenced by the increased sub-G1 population and PARP cleavage. The expression levels of YAP and its target genes were highly correlated with poor prognosis and predicted a high risk of HCC patients. These findings collectively suggest that statins utilization maybe a promising new strategy to counteract hypoxia-mediated resistance to sorafenib in HCC patients.
authors.affiliation: Zhejiang Province Key Laboratory of anti-cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical sciences, Zhejiang University, Hangzhou, China.
authors.forename: Tian-Yi
authors.initials: TY
authors.lastname: Zhou
authors.affiliation: Zhejiang Province Key Laboratory of anti-cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical sciences, Zhejiang University, Hangzhou, China.
authors.forename: Lin-Han
authors.initials: LH
authors.lastname: Zhuang
authors.affiliation: Zhejiang Province Key Laboratory of anti-cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical sciences, Zhejiang University, Hangzhou, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Zhejiang Province Key Laboratory of anti-cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical sciences, Zhejiang University, Hangzhou, China.
authors.forename: Yu-Lu
authors.initials: YL
authors.lastname: Zhou
authors.affiliation: Zhejiang Province Key Laboratory of anti-cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical sciences, Zhejiang University, Hangzhou, China.
authors.forename: Wen-Kai
authors.initials: WK
authors.lastname: Lin
authors.affiliation: Zhejiang Province Key Laboratory of anti-cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical sciences, Zhejiang University, Hangzhou, China.
authors.forename: Dan-Dan
authors.initials: DD
authors.lastname: Wang
authors.affiliation: Zhejiang Province Key Laboratory of anti-cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical sciences, Zhejiang University, Hangzhou, China.
authors.forename: Zi-Qian
authors.initials: ZQ
authors.lastname: Wan
authors.affiliation: Zhejiang Province Key Laboratory of anti-cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical sciences, Zhejiang University, Hangzhou, China.
authors.forename: Lin-Lin
authors.initials: LL
authors.lastname: Chang
authors.affiliation: Zhejiang Province Key Laboratory of anti-cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical sciences, Zhejiang University, Hangzhou, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Zhejiang Province Key Laboratory of anti-cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical sciences, Zhejiang University, Hangzhou, China.
authors.forename: Mei-Dan
authors.initials: MD
authors.lastname: Ying
authors.affiliation: Zhejiang Province Key Laboratory of anti-cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical sciences, Zhejiang University, Hangzhou, China.
authors.forename: Zi-Bo
authors.initials: ZB
authors.lastname: Chen
authors.affiliation: First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Song
authors.initials: S
authors.lastname: Ye
authors.affiliation: Zhejiang Province Key Laboratory of anti-cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical sciences, Zhejiang University, Hangzhou, China.
authors.forename: Jian-Shu
authors.initials: JS
authors.lastname: Lou
authors.affiliation: Zhejiang Province Key Laboratory of anti-cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical sciences, Zhejiang University, Hangzhou, China.
authors.forename: Qiao-Jun
authors.initials: QJ
authors.lastname: He
authors.affiliation: Zhejiang Province Key Laboratory of anti-cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical sciences, Zhejiang University, Hangzhou, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Zhejiang Province Key Laboratory of anti-cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical sciences, Zhejiang University, Hangzhou, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000069059:Atorvastatin / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D008819:Mice, Nude; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D021381:Protein Transport / Q000187:drug effects; D000077157:Sorafenib; D014157:Transcription Factors; D023041:Xenograft Model Antitumor Assays; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010671:Phenylurea Compounds; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D009536:Niacinamide; D000077157:Sorafenib; D000069059:Atorvastatin