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First published on March 30, 2007; DOI: 10.1124/mol.106.029025

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Received for publication August 8, 2006.
Revised March 29, 2007.
Accepted for publication March 30, 2007.

Inhibition of TGF{beta} signaling reduces pancreatic adenocarcinoma growth and invasiveness

Nicholas J Gaspar 1*, Lingyun Li 2, Ann M Kapoun 2, Satyanarayana Medicherla 2, Mamatha Reddy 2, Georgia Li 2, Gilbert O'Young 2, Diana Quon 2, Margaret Henson 2, Deborah L Damm 2, Gladys T Muiru 2, Alison Murphy 2, Linda S Higgins 2, Sarvajit Chakravarty 2, Darren H Wong 2

1 Scios Inc. 2 Scios Inc

* Address correspondence to: E-mail: gaspar.nj{at}gmail.com

Abstract

Transforming growth factor {beta}(TGF{beta}) is a pleiotropic factor that regulates cell proliferation, angiogenesis, metastasis, and immune suppression. Dysregulation of the TGF{beta} pathway in tumor cells often leads to resistance to the anti-proliferative effects of TGF{beta} while supporting other cellular processes that promote tumor invasiveness and growth. In the present study SD-208, a small molecule, ATP-competitive inhibitor of the TGF{beta} receptor I kinase (TGF{beta}RI), was used to inhibit cellular activities and tumor progression of PANC-1, a human pancreatic tumor line. SD-208 blocked TGF{beta}-dependent Smad2 phosphorylation and expression of TGF{beta}-inducible proteins in cell culture. cDNA microarray analysis and functional gene clustering identified groups of TGF{beta}-regulated genes involved in metastasis, angiogenesis, cell proliferation, survival, and apoptosis. These gene responses were inhibited by SD-208. Using a Boyden chamber motility assay, we demonstrated that SD-208 inhibited TGF{beta}-stimulated invasion in vitro. An orthotopic xenograft mouse model revealed that SD-208 reduced primary tumor growth and decreased the incidence of metastasis in vivo. Our findings suggest mechanisms through which TGF{beta} signaling may promote tumor progression in pancreatic adenocarcinoma. Moreover, they suggest that inhibition of TGF{beta}RI with a small molecule inhibitor may be effective as a therapeutic approach to treat human pancreatic cancer.


Key words: Insulin, Ras, MAP Kinase, Regulation of gene expression, Apoptosis, Mechanisms of cell killing/apoptosis, Metastasis, Oncogenes, Tumor suppressors, Angiogenesis


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