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Chemical Enhancers of Cytokine Signaling that Suppress Microfilament Turnover and Tumor Cell Growth

¹ Samuel Lunenfeld Research Institute, Mount Sinai Hospital; Departments of ² Medical Genetics and Microbiology and ³ Laboratory Medicine and Pathology, University of Toronto, Toronto, Ontario, Canada

Requests for reprints: James W. Dennis, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue R988, Toronto, Ontario, Canada M5G 1X5. Phone: 416-586-8233; Fax: 416-586-8857; E-mail: Dennis{at}mshri.on.ca.

The transforming growth factor-ß (TGF-ß) family of cytokines regulates cell proliferation, morphogenesis, and specialized cell functions in metazoans. Herein, we screened a compound library for modifiers of TGF-ß signaling in NMuMG epithelial cells using a cell-based assay to measure Smad2/3 nuclear translocation. We identified five enhancers of TGF-ß signaling that share a core structure of diethyl 2-(anilinomethylene)malonate (DAM), and D₅₀ values of 1 to 4 µmol/L. Taking advantage of the Mgat5 mutant phenotype of accelerated receptor loss to endocytosis, we determined that DAM-1976 restored the sensitivity of Mgat5^–/– carcinoma cells to both TGF-ß and epidermal growth factor (EGF). In Mgat5 mutant and wild-type carcinoma cells, DAM-1976 enhanced and prolonged TGF-ß- and EGF-dependent Smad2/3 and Erk activation, respectively. DAM-1976 reduced ligand-dependent EGF receptor endocytosis, actin microfilament turnover, and cell spreading, suggesting that the compound attenuates vesicular trafficking. Hyperactivation of intracellular signaling has the potential to suppress tumor cell growth and, in this regard, DAM-1976 represents a new pharmacophore that increases basal activation of Smad2/3 and Erk, inhibits microfilament remodeling, and suppresses carcinoma cell growth. (Cancer Res 2006; 66(7): 3558-66)

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