The Src Family Kinase Inhibitors PP2 and PP1 Block TGF-Beta1-Mediated Cellular Responses by Direct and Differential Inhibition of Type I and Type II TGF-Beta Receptors

Publisher： Bentham Science Publishers

E-ISSN： 1873-5576|11|4|524-535

ISSN： 1568-0096

Source： Current Cancer Drug Targets, Vol.11, Iss.4, 2011-05, pp. : 524-535

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Abstract

Both the nonreceptor tyrosine kinase Src and the receptors for transforming growth factor (TGF)-&bgr; (T&bgr;RI, T&bgr;RII) play major roles during tumorigenesis by regulating cell growth, migration/invasion and metastasis. The common Src family kinase inhibitors PP2 and PP1 effectively block Src activity in vitro and in vivo, however, they may exert nonspecific effects on other kinases. In this study, we have evaluated PP2 and PP1 for their ability to inhibit TGF&bgr;1-mediated responses in the TGF-&bgr;-responsive pancreatic adenocarcinoma cell line Panc1. We show that PP2 and PP1 but not the more specific Src inhibitor SU6656 effectively relieved TGF-&bgr;1-induced growth arrest and p21WAF1 induction, while basal growth was enhanced by PP2 and PP1, and suppressed by SU6656. PP2 and PP1 but not SU6656 also suppressed TGF-&bgr;1-induced epithelial-to-mesenchymal transition (EMT) as evidenced by their ability to inhibit downregulation of the epithelial marker E-cadherin, and upregulation of the EMT-associated transcription factor Slug. Likewise, PP2 and PP1 but not SU6656 effectively blocked TGF-&bgr;1-induced activation of Smad2 and p38 MAPK and partially suppressed Smad activation and transcriptional activity on TGF-&bgr;/Smad-responsive reporters of a kinase-active T&bgr;RI mutant ectopically expressed in Panc1 cells. Interestingly, PP2 and PP1 strongly inhibited recombinant T&bgr;RI in an in vitro kinase assay, with PP1 being more potent and PP2 being nearly as potent as the established T&bgr;RI inhibitor SB431542. PP2 but not PP1 also weakly inhibited the T&bgr;RII kinase. Together, these data provide evidence that PP2 and PP1 are powerful inhibitors of T&bgr;R function that can block TGF-&bgr;/Smad signaling in a Src-unrelated fashion. Both agents may be useful as dual TGF-&bgr;/Src inhibitors in experimental therapeutics of late stage metastatic disease.