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

Evason, K.J., Francisco, M.T., Juric, V., Balakrishnan, S., Lopez Pazmino, M.D., Gordan, J.D., Kakar, S., Spitsbergen, J., Goga, A., Stainier, D.Y.
PLoS Genetics   11: e1005305 (Journal)
Registered Authors
Evason, Kimberley, Stainier, Didier
MeSH Terms
  • Amitriptyline/therapeutic use*
  • Animals
  • Animals, Genetically Modified
  • Antidepressive Agents, Tricyclic/therapeutic use*
  • Carcinoma, Hepatocellular/drug therapy*
  • Carcinoma, Hepatocellular/mortality
  • Carcinoma, Hepatocellular/pathology
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic/drug effects
  • Disease Models, Animal
  • Gene Expression Regulation, Neoplastic
  • Hepatocytes/metabolism
  • Hepatocytes/pathology
  • Humans
  • JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors
  • JNK Mitogen-Activated Protein Kinases/metabolism
  • Liver/pathology
  • Liver Neoplasms/drug therapy*
  • Liver Neoplasms/mortality
  • Liver Neoplasms/pathology
  • MAP Kinase Signaling System/drug effects
  • Mice
  • Serotonin Uptake Inhibitors/therapeutic use
  • Xenopus laevis
  • Zebrafish
  • beta Catenin/genetics
  • beta Catenin/metabolism*
26134322 Full text @ PLoS Genet.
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.
Genes / Markers
Show all Figures
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes