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

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.

• Authors: Dipanjan Basu, Robert Lettan, Krishnan Damodaran, Susan Strellec, Miguel Reyes-Mugica, Abdelhadi Rebbaa
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 13 Issue 6 Pg. 1457-67 (Jun 2014) ISSN: 1538-8514 [Electronic] United States
• PMID: 24694946 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Propanols
• Thiadiazoles
• Transcription Factors
• Transforming Growth Factor beta
• Acyltransferases
• TAFAZZIN protein, human
• Protein Serine-Threonine Kinases
• Glycogen Synthase Kinase 3
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (metabolism)
• Acyltransferases
• Animals
• Antineoplastic Agents (administration & dosage)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Epithelial-Mesenchymal Transition (drug effects)
• Glycogen Synthase Kinase 3 (metabolism)
• Hippo Signaling Pathway
• Humans
• Mice
• Neoplasm Recurrence, Local (drug therapy, genetics, metabolism)
• Neoplasms (drug therapy, metabolism)
• Propanols (administration & dosage)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Thiadiazoles (administration & dosage)
• Transcription Factors (metabolism)
• Transforming Growth Factor beta (antagonists & inhibitors, metabolism)
• Wnt Signaling Pathway (drug effects)