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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Yearbook 2016     Display Documents



ID: 723995.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Yearbook 2016
Identification of Chemical Inhibitors of beta-Catenin-Driven Liver Tumorigenesis in Zebrafish
Authors:Evason, K. J.; Francisco, M. T.; Juric, V.; Balakrishnan, S.; Lopez Pazmino Mdel, P.; Gordan, J. D.; Kakar, S.; Spitsbergen, J.; Goga, A.; Stainier, D. Y.
Date of Publication (YYYY-MM-DD):2015-07
Title of Journal:PLoS Genet
Volume:11
Issue / Number:7
Start Page:e1005305
Audience:Not Specified
Abstract / Description: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 beta-catenin. To address this chemotherapeutic challenge, we created and characterized transgenic zebrafish expressing hepatocyte-specific activated beta-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 beta-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 beta-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 beta-catenin. The beta-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 beta-catenin-induced liver tumors.
External Publication Status:published
Document Type:Article
Communicated by:n.n.
Affiliations:MPI für physiologische und klinische Forschung
External Affiliations: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. The George Williams Hooper Research Foundation, 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. 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. Department of Medicine, University of California, San Francisco, San Francisco, California, United States of America. Department of Pathology, University of California, San Francisco, San Francisco, California, United States of America. Department of Microbiology, Oregon State University, Corvallis, Oregon, United States of America. 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.
Identifiers:ISSN:1553-7404 (Electronic) 1553-7390 (Linking) %R 10.1371/journal.pgen.1005305
URL:http://www.ncbi.nlm.nih.gov/pubmed/26134322
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