title: Tankyrase inhibitors attenuate WNT/β-catenin signaling and inhibit growth of hepatocellular carcinoma cells.
abstract: Deregulated WNT/β-catenin signaling contributes to the development of a subgroup of hepatocellular carcinoma (HCC), the second leading cause of cancer deaths worldwide. Within this pathway, the tankyrase enzymes (TNKS1 and TNKS2) degrade AXIN and thereby enhance β-catenin activity. We evaluate TNKS enzymes as potential therapeutic targets in HCC, and the anti-tumor efficacy of tankyrase inhibitors (XAV939, and its novel nitro-substituted derivative WXL-8) in HCC cells. Using semi-quantitative RT-PCR, we found significantly elevated levels of TNKS1/2 mRNA in tumor liver tissues compared to adjacent non-tumor livers, at protein levels only TNKS1 is increased. In HepG2, Huh7cells, siRNA-mediated knockdown suppression of endogenous TNKS1 and TNKS2 reduced cell proliferation, together with decreased nuclear β-catenin levels. XAV939 and WXL-8 inhibited cell proliferation and colony formation in HepG2, Huh7, and Hep40 cells (p < 0.05), with stabilization of AXIN1 and AXIN2, and decreased β-catenin protein levels. XAV939 and WXL-8 also attenuated rhWNT3A-induced TOPflash luciferase reporter activity in HCC cells, indicating reduced β-catenin transcriptional activity, consistent with decreased nuclear β-catenin levels. In vivo, intra-tumor injections of XAV939 or WXL-8 significantly inhibited the growth of subcutaneous HepG2 xenografts (P < 0.05). We suggest that tankyrase inhibition is a potential therapeutic approach for treating a subgroup HCC with aberrant WNT/β-catenin signaling pathway.
authors.affiliation: Asian Liver Center and Department of Surgery, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.affiliation: Asian Liver Center and Department of Surgery, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA.|Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510655, China.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Wuhan University, Wuhan, Hubei, 430072, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Jia
authors.affiliation: Asian Liver Center and Department of Surgery, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.affiliation: Asian Liver Center and Department of Surgery, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Mei-Sze
authors.initials: MS
authors.lastname: Chua
authors.affiliation: Asian Liver Center and Department of Surgery, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: So
mesh_terms: D000818:Animals; D060466:Axin Protein / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D056945:Hep G2 Cells; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D055550:Protein Stability; D034622:RNA Interference; D038501:Tankyrases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D060509:Wnt3A Protein / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D060466:Axin Protein; D006575:Heterocyclic Compounds, 3-Ring; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D038501:Tankyrases; D060509:Wnt3A Protein; D051176:beta Catenin; C555451:AXIN1 protein, human; C491761:AXIN2 protein, human; C495270:CTNNB1 protein, human; C555510:WNT3A protein, human; C544261:XAV939; C437334:TNKS2 protein, human; C418109:TNKS protein, human
keywords: WNT/β-catenin signaling; hepatocellular carcinoma; tankyrase inhibitors; targeted therapy; β-catenin/TCF complexes