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Mol Cancer Ther. 2014 Jun;13(6):1457-67. doi: 10.1158/1535-7163.MCT-13-0918. Epub 2014 Apr 2.

Identification, mechanism of action, and antitumor activity of a small molecule inhibitor of hippo, TGF-β, and Wnt signaling pathways.

Author information

1
Authors' Affiliations: Department of Pathology, University of Pittsburgh and the Children's Hospital of Pittsburgh of UPMC; Department of Chemistry, University of Pittsburgh; and Department of Chemistry, Chatham University, Pittsburgh, Pennsylvania.
2
Authors' Affiliations: Department of Pathology, University of Pittsburgh and the Children's Hospital of Pittsburgh of UPMC; Department of Chemistry, University of Pittsburgh; and Department of Chemistry, Chatham University, Pittsburgh, Pennsylvania abr25@pitt.edu.

Abstract

Embryonic signaling pathways, in particular those mediated by Wnt and TGF-β, are known to play key roles in tumor progression through the induction of epithelial-mesenchymal transition (EMT). Their simultaneous targeting could therefore represent a desirable anticancer strategy. On the basis of recent findings that both Wnt and TGF-β-associated pathways are regulated by Hippo signaling in mammalian cells, we reasoned that targeting the latter would be more effective in inhibiting EMT. In a search for such inhibitors, we identified a small molecule (C19) with remarkable inhibitory activity not only against Hippo, but also against Wnt and TGF-β pathways. C19 inhibited cancer cell migration, proliferation, and resistance to doxorubicin in vitro, and exerted strong antitumor activity in a mouse tumor model. Mechanistically, C19 induced GSK3-β-mediated degradation of the Hippo transducer TAZ, through activation of the Hippo kinases Mst/Lats and the tumor suppressor kinase AMPK upstream of the degradation complex. Overall, this study identified C19 as a multi-EMT pathway inhibitor with a unique mechanism of action. The findings that both AMPK and Mst/Lats mediate the antitumor activity of C19 shed light on a potential cross-talk between metabolic and organ size control pathways in regulating cancer progression. By simultaneously targeting these two pathways, C19 may represent a new type of agents to suppress cancer progression and/or its recurrence.

PMID:
24694946
DOI:
10.1158/1535-7163.MCT-13-0918
[Indexed for MEDLINE]
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