Inhibition of transforming growth factor beta signaling reduces pancreatic adenocarcinoma growth and invasiveness.
Transforming growth factor beta (TGFbeta) is a pleiotropic factor that regulates cell proliferation, angiogenesis, metastasis, and immune suppression. Dysregulation of the TGFbeta pathway in tumor cells often leads to resistance to the antiproliferative effects of TGFbeta 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 TGFbeta receptor I kinase (TGFbetaRI), was used to inhibit cellular activities and tumor progression of PANC-1, a human pancreatic tumor line. SD-208 blocked TGFbeta-dependent Smad2 phosphorylation and expression of TGFbeta-inducible proteins in cell culture. cDNA microarray analysis and functional gene clustering identified groups of TGFbeta-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 TGFbeta-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 TGFbeta signaling may promote tumor progression in pancreatic adenocarcinoma. Moreover, they suggest that inhibition of TGFbetaRI with a small-molecule inhibitor may be effective as a therapeutic approach to treat human pancreatic cancer.
Gaspar
Nicholas J
NJ
Scios Inc., Fremont, CA, USA. gaspar.nj@gmail.com
Li
Lingyun
L
Kapoun
Ann M
AM
Medicherla
Satyanarayana
S
Reddy
Mamatha
M
Li
Georgia
G
O'Young
Gilbert
G
Quon
Diana
D
Henson
Margaret
M
Damm
Deborah L
DL
Muiru
Gladys T
GT
Murphy
Alison
A
Higgins
Linda S
LS
Chakravarty
Sarvajit
S
Wong
Darren H
DH
D030201:Activin Receptors, Type I / Q000037:antagonists & inhibitors; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016259:Genes, myc; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017346:Protein Serine-Threonine Kinases; D011621:Pteridines / Q000494:pharmacology* / Q000627:therapeutic use; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects*; D051899:Smad2 Protein / Q000037:antagonists & inhibitors; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics
D011621:Pteridines; D018125:Receptors, Transforming Growth Factor beta; C511004:SD-208; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I