PMID- 24694946 OWN - NLM STAT- MEDLINE DCOM- 20150219 LR - 20211203 IS - 1538-8514 (Electronic) IS - 1535-7163 (Linking) VI - 13 IP - 6 DP - 2014 Jun TI - Identification, mechanism of action, and antitumor activity of a small molecule inhibitor of hippo, TGF-beta, and Wnt signaling pathways. PG - 1457-67 LID - 10.1158/1535-7163.MCT-13-0918 [doi] AB - Embryonic signaling pathways, in particular those mediated by Wnt and TGF-beta, 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-beta-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-beta 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-beta-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. CI - (c)2014 American Association for Cancer Research. FAU - Basu, Dipanjan AU - Basu D AD - 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. FAU - Lettan, Robert AU - Lettan R AD - 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. FAU - Damodaran, Krishnan AU - Damodaran K AD - 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. FAU - Strellec, Susan AU - Strellec S AD - 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. FAU - Reyes-Mugica, Miguel AU - Reyes-Mugica M AD - 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. FAU - Rebbaa, Abdelhadi AU - Rebbaa A AD - 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. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140402 PL - United States TA - Mol Cancer Ther JT - Molecular cancer therapeutics JID - 101132535 RN - 0 (Antineoplastic Agents) RN - 0 (Propanols) RN - 0 (Thiadiazoles) RN - 0 (Transcription Factors) RN - 0 (Transforming Growth Factor beta) RN - EC 2.3.- (Acyltransferases) RN - EC 2.3.1.- (TAFAZZIN protein, human) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.26 (Glycogen Synthase Kinase 3) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) SB - IM MH - AMP-Activated Protein Kinases/metabolism MH - Acyltransferases MH - Animals MH - Antineoplastic Agents/*administration & dosage MH - Cell Line, Tumor MH - Cell Movement/drug effects MH - Epithelial-Mesenchymal Transition/drug effects MH - Glycogen Synthase Kinase 3/metabolism MH - Hippo Signaling Pathway MH - Humans MH - Mice MH - Neoplasm Recurrence, Local/drug therapy/genetics/metabolism MH - Neoplasms/*drug therapy/metabolism MH - Propanols/*administration & dosage MH - Protein Serine-Threonine Kinases/antagonists & inhibitors/*metabolism MH - Thiadiazoles/*administration & dosage MH - Transcription Factors/metabolism MH - Transforming Growth Factor beta/antagonists & inhibitors/*metabolism MH - Wnt Signaling Pathway/drug effects EDAT- 2014/04/04 06:00 MHDA- 2015/02/20 06:00 CRDT- 2014/04/04 06:00 PHST- 2014/04/04 06:00 [entrez] PHST- 2014/04/04 06:00 [pubmed] PHST- 2015/02/20 06:00 [medline] AID - 1535-7163.MCT-13-0918 [pii] AID - 10.1158/1535-7163.MCT-13-0918 [doi] PST - ppublish SO - Mol Cancer Ther. 2014 Jun;13(6):1457-67. doi: 10.1158/1535-7163.MCT-13-0918. Epub 2014 Apr 2.