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Supplementary Figure 5 from Identification, Mechanism of Action, and Antitumor Activity of a Small Molecule Inhibitor of Hippo, TGF-β, and Wnt Signaling Pathways

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posted on 2023-04-03, 14:04 authored by Dipanjan Basu, Robert Lettan, Krishnan Damodaran, Susan Strellec, Miguel Reyes-Mugica, Abdelhadi Rebbaa

PDF - 65K, Regulation of C19 activity by TDZD and rapamycin.

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ARTICLE 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. Mol Cancer Ther; 13(6); 1457–67. ©2014 AACR.

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    Molecular Cancer Therapeutics

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    AngiogenesisAngiogenesis mechanismsCell CycleCyclinsCell SignalingDrug Discovery TechnologiesScreening strategies (assays and chemical libraries)Drug MechanismsCellular responses to anticancer drugsDrug TargetsGastrointestinal CancersColorectal cancerProgression, Invasion & MetastasisMigration and invasionSkin Cancers

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