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Identification of Chemical Inhibitors of β-Catenin-Driven Liver Tumorigenesis in Zebrafish

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https://ir.library.oregonstate.edu/concern/articles/tm70mx021

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  • 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.
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  • Evason, K. J., Francisco, M. T., Juric, V., Balakrishnan, S., Pazmino, M. D. P. L., Gordan, J. D., ... & Stainier, D. Y. (2015). Identification of chemical inhibitors of β-catenin-driven liver tumorigenesis in zebrafish. PLoS Genetics, 11(7), e1005305. doi:10.1371/journal.pgen.1005305
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  • 11
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  • 7
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  • This project was funded in part through the UCSF Cancer Center and UCSF Academic Senate. KJE was a Robert Black Fellow supported by the Damon Runyon Cancer Research Foundation (DRG-109-10) and is currently supported by NIH NCI 5K08CA172288. MdPLP is supported by NIH NIGMS MARC: T34-GM008574. JDG is supported by an American Cancer Society Postdoctoral Fellowship. JS is supported by the Agricultural Research Foundation of Oregon and the John Fryer Salmon Disease Laboratory of the Department of Microbiology at Oregon State University. AG is supported by a V-Foundation Scholar Award and NIH NCI R01-CA170447. This project was supported in part by the UCSF Liver Center, including a Pilot/Feasibility Award (NIH P30DK026743) to Chunyue Yin and a Tools and Technology Grant to DYRS, and grants from the NIH (DK60322) and the Packard Foundation to DYRS. Flow cytometry was performed at the UCSF Parnassus Flow Cytometry Core, funded in part by Diabetes Research Center (DRC) grant, NIH P30 DK063720.
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file details SpitsbergenJanMicrobiologyIdentificationChemicalInhibitors.pdf 2017-07-25 Pubblico Scaricare