Identification, mechanism of action, and antitumor activity of a small molecule inhibitor of hippo, TGF-β, and Wnt signaling pathways.
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' 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.
Dipanjan
D
Basu
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.
Robert
R
Lettan
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.
Krishnan
K
Damodaran
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.
Susan
S
Strellec
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.
Miguel
M
Reyes-Mugica
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.
Abdelhadi
A
Rebbaa
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000217:Acyltransferases; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000090683:Hippo Signaling Pathway; D006801:Humans; D051379:Mice; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D020005:Propanols / Q000008:administration & dosage*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013830:Thiadiazoles / Q000008:administration & dosage*; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects
D000970:Antineoplastic Agents; D020005:Propanols; D013830:Thiadiazoles; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000217:Acyltransferases; C108675:TAFAZZIN protein, human; D017346:Protein Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3; D055372:AMP-Activated Protein Kinases