Chemical enhancers of cytokine signaling that suppress microfilament turnover and tumor cell growth.

Abstract:

:The transforming growth factor-beta (TGF-beta) family of cytokines regulates cell proliferation, morphogenesis, and specialized cell functions in metazoans. Herein, we screened a compound library for modifiers of TGF-beta signaling in NMuMG epithelial cells using a cell-based assay to measure Smad2/3 nuclear translocation. We identified five enhancers of TGF-beta signaling that share a core structure of diethyl 2-(anilinomethylene)malonate (DAM), and D(50) values of 1 to 4 micromol/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-beta and epidermal growth factor (EGF). In Mgat5 mutant and wild-type carcinoma cells, DAM-1976 enhanced and prolonged TGF-beta- 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.

journal_name

Cancer Res

journal_title

Cancer research

authors

Park HJ,Partridge E,Cheung P,Pawling J,Donovan R,Wrana JL,Dennis JW

doi

10.1158/0008-5472.CAN-05-2542

subject

Has Abstract

pub_date

2006-04-01 00:00:00

pages

3558-66

issue

7

eissn

0008-5472

issn

1538-7445

pii

66/7/3558

journal_volume

66

pub_type

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