Inhibition of Transforming Growth Factor β Signaling Reduces Pancreatic Adenocarcinoma Growth and Invasiveness

Open Access
Publisher Website
Google Scholar
Abstract
Transforming growth factor β (TGFβ) is a pleiotropic factor that regulates cell proliferation, angiogenesis, metastasis, and immune suppression. Dysregulation of the TGFβ pathway in tumor cells often leads to resistance to the antiproliferative effects of TGFβ while supporting other cellular processes that promote tumor invasiveness and growth. In the present study, SD-208, a 2,4-disubstituted pteridine, ATP-competitive inhibitor of the TGFβ receptor I kinase (TGFβRI), was used to inhibit cellular activities and tumor progression of PANC-1, a human pancreatic tumor line. SD-208 blocked TGFβ-dependent Smad2 phosphorylation and expression of TGFβ-inducible proteins in cell culture. cDNA microarray analysis and functional gene clustering identified groups of TGFβ-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 TGFβ-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 TGFβ signaling may promote tumor progression in pancreatic adenocarcinoma. Moreover, they suggest that inhibition of TGFβRI with a small-molecule inhibitor may be effective as a therapeutic approach to treat human pancreatic cancer.