Inhibition of transforming growth factor β signaling reduces pancreatic adenocarcinoma growth and invasiveness

被引：107

作者：

Gaspar, Nicholas J. ^{[1
]}

Li, Lingyun ^{[1
]}

Kapoun, Ann M. ^{[1
]}

Medicherla, Satyanarayana ^{[1
]}

Reddy, Mamatha ^{[1
]}

Li, Georgia ^{[1
]}

O'Young, Gilbert ^{[1
]}

Quon, Diana ^{[1
]}

Henson, Margaret ^{[1
]}

Damm, Deborah L. ^{[1
]}

Muiru, Gladys T. ^{[1
]}

Murphy, Alison ^{[1
]}

Higgins, Linda S. ^{[1
]}

Chakravarty, Sarvajit ^{[1
]}

Wong, Darren H. ^{[1
]}

机构：

[1] Scios Inc, Fremont, CA USA

来源：

MOLECULAR PHARMACOLOGY | 2007年 / 72卷 / 01期

关键词：

IMMEDIATE-EARLY GENE; CELLS IN-VITRO; VEGF-C; CANCER; EXPRESSION; KINASE; METASTASIS; IMMUNOGENICITY; PROLIFERATION; DISRUPTION;

D O I：

10.1124/mol.106.029025

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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 antiproliferative effects of TGF beta 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 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.

引用

页码：152 / 161

页数：10

共 42 条

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