title: Identification of Chemical Inhibitors of β-Catenin-Driven Liver Tumorigenesis in Zebrafish.
abstract: Hepatocellular carcinoma (HCC) is one of the most lethal human cancers. The search for targeted treatments has been hampered by the lack of relevant animal models for the genetically diverse subsets of HCC, including the 20-40% of HCCs that are defined by activating mutations in the gene encoding β-catenin. To address this chemotherapeutic challenge, we created and characterized transgenic zebrafish expressing hepatocyte-specific activated β-catenin. By 2 months post fertilization (mpf), 33% of transgenic zebrafish developed HCC in their livers, and 78% and 80% of transgenic zebrafish showed HCC at 6 and 12 mpf, respectively. As expected for a malignant process, transgenic zebrafish showed significantly decreased mean adult survival compared to non-transgenic control siblings. Using this novel transgenic model, we screened for druggable pathways that mediate β-catenin-induced liver growth and identified two c-Jun N-terminal kinase (JNK) inhibitors and two antidepressants (one tricyclic antidepressant, amitriptyline, and one selective serotonin reuptake inhibitor) that suppressed this phenotype. We further found that activated β-catenin was associated with JNK pathway hyperactivation in zebrafish and in human HCC. In zebrafish larvae, JNK inhibition decreased liver size specifically in the presence of activated β-catenin. The β-catenin-specific growth-inhibitory effect of targeting JNK was conserved in human liver cancer cells. Our other class of hits, antidepressants, has been used in patient treatment for decades, raising the exciting possibility that these drugs could potentially be repurposed for cancer treatment. In support of this proposal, we found that amitriptyline decreased tumor burden in a mouse HCC model. Our studies implicate JNK inhibitors and antidepressants as potential therapeutics for β-catenin-induced liver tumors.
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, California, United States of America; Department of Biochemistry and Biophysics, Programs in Developmental and Stem Cell Biology, Genetics and Human Genetics, Diabetes Center, Institute for Regeneration Medicine and the Liver Center, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Kimberley J
authors.initials: KJ
authors.lastname: Evason
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, California, United States of America; Department of Cell & Tissue Biology, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Macrina T
authors.initials: MT
authors.lastname: Francisco
authors.affiliation: The George Williams Hooper Research Foundation, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Vladislava
authors.initials: V
authors.lastname: Juric
authors.affiliation: Department of Cell & Tissue Biology, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Balakrishnan
authors.affiliation: Department of Biochemistry and Biophysics, Programs in Developmental and Stem Cell Biology, Genetics and Human Genetics, Diabetes Center, Institute for Regeneration Medicine and the Liver Center, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Maria Del Pilar
authors.initials: Mdel P
authors.lastname: Lopez Pazmino
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: John D
authors.initials: JD
authors.lastname: Gordan
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Kakar
authors.affiliation: Department of Microbiology, Oregon State University, Corvallis, Oregon, United States of America.
authors.forename: Jan
authors.initials: J
authors.lastname: Spitsbergen
authors.affiliation: Department of Cell & Tissue Biology, University of California, San Francisco, San Francisco, California, United States of America; Department of Medicine, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Andrei
authors.initials: A
authors.lastname: Goga
authors.affiliation: Department of Biochemistry and Biophysics, Programs in Developmental and Stem Cell Biology, Genetics and Human Genetics, Diabetes Center, Institute for Regeneration Medicine and the Liver Center, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Didier Y R
authors.initials: DY
authors.lastname: Stainier
mesh_terms: D000639:Amitriptyline / Q000627:therapeutic use*; D000818:Animals; D030801:Animals, Genetically Modified; D000929:Antidepressive Agents, Tricyclic / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D000090204:Mesothelin; D051379:Mice; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use; D014982:Xenopus laevis; D015027:Zebrafish; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D000639:Amitriptyline; D000929:Antidepressive Agents, Tricyclic; D048031:JNK Mitogen-Activated Protein Kinases; D000090204:Mesothelin; D017367:Selective Serotonin Reuptake Inhibitors; D051176:beta Catenin; C000715528:Msln protein, mouse