title: Inhibition of the Wnt/β-catenin signaling pathway improves the anti-tumor effects of sorafenib against hepatocellular carcinoma.
abstract: Sorafenib, a multikinase inhibitor, is currently the only approved drug for advanced hepatocellular carcinoma (HCC). The current study tested the hypothesis whether inhibition of the Wnt/β-catenin signaling pathway could improve the anti-tumor effects of sorafenib in HCC. ICG-001, a small molecule which blocks the interaction of β-catenin with its transcriptional coactivator CBP, dose-dependently enhanced the growth-suppressive and apoptosis-induction effects of sorafenib in multiple HCC cell lines. Downregulation of β-catenin by RNA interference increased sorafenib sensitivity, whereas overexpression of β-catenin reduced sorafenib sensitivity in Huh7 cells. The sorafenib-sensitization effect of short hairpin RNA (shRNA)-mediated β-catenin downregulation in Huh7 cells was attenuated by β-catenin overexpression. Mechanistically, sorafenib combined with ICG-001 or shRNA-mediated β-catenin downregulation augmented the induction of apoptosis, and resulted in a significant downregulation of Mcl-1 in HCC cells. In Huh7 cell mouse xenograft model, the combination of ICG-001 and sorafenib showed a more significant growth-retarding effect than single agent treatment of sorafenib or ICG-001. Our data indicate that inhibition of the Wnt/β-catenin signaling pathway improves the antitumor effects of sorafenib against HCC in vitro and in vivo.
authors.affiliation: Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Hsiao-Hui
authors.initials: HH
authors.lastname: Lin
authors.affiliation: Graduate Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Wen-Chi
authors.initials: WC
authors.lastname: Feng
authors.affiliation: Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Li-Chun
authors.initials: LC
authors.lastname: Lu
authors.affiliation: Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; National Taiwan University Cancer Center, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Yu-Yun
authors.initials: YY
authors.lastname: Shao
authors.affiliation: Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan. Electronic address: chihhunghsu@ntu.edu.tw.
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Hsu
authors.affiliation: Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; National Taiwan University Cancer Center, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Ann-Lii
authors.initials: AL
authors.lastname: Cheng
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*; D034622:RNA Interference; D000067492:RNAi Therapeutics; D000077157:Sorafenib; D014162:Transfection; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D019086:Bridged Bicyclo Compounds, Heterocyclic; C495270:CTNNB1 protein, human; C492448:ICG 001; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011744:Pyrimidinones; D051176:beta Catenin; D009536:Niacinamide; D000077157:Sorafenib
keywords: Hepatocellular carcinoma; ICG-001; Sorafenib; Wnt/β-catenin