Neuropilin-1 interacts with integrin beta1 and modulates pancreatic cancer cell growth, survival and invasion.
Neuropilin-1 (Np-1) is a coreceptor for vascular endothelial growth factor-A (VEGF-A), and both are expressed at high levels in pancreatic ductal adenocarcinomas (PDACs). While VEGF-A has been implicated in tumor angiogenesis, the role of Np-1 in PDAC is less clearly defined. Accordingly, PANC-1 pancreatic cancer cells, which express relatively high levels of Np-1, were transfected with the Np-1 antisense cDNA. By comparison with sham transfected cells, Np-1 antisense expressing clones (Np-1AS) exhibited decreased anchorage independent growth, adhesion and invasiveness, and prolonged doubling times. Np-1AS were also more sensitive to the pro-apoptotic actions of ActD, as evidenced by PARP cleavage, caspase 9 activation and annexin V staining. ActD decreased Bcl-xL and STAT5 levels in the antisense expressing cells, but not in sham-transfected cells, and did not alter STAT3, Bcl-2, phospho-AKT, AKT, Bad, Bax or Bak levels. Immunoprecipitation followed by immunoblotting revealed that Np-1 associated with integrin beta1 and integrin beta1 blockade attenuated adhesion. However, Np-AS expressing clones exhibited enhanced tyrosine phosphorylated focal adhesion kinase. Thus, Np-1 confers a growth and survival advantage to PANC-1 cells, and interacts with integrin beta1 to coordinate signaling events that promote cell adherence and invasiveness.
Fukasawa
Mitsuharu
M
Department of Medicine, Pharmacology and Toxicology, and the Norris Cotton Comprehensive Cancer Center, Hanover, New Hampshire New Hampshire, USA.
Matsushita
Akira
A
Korc
Murray
M
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D016373:DNA, Antisense / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D039942:Neuropilin-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D051017:Apoptosis Regulatory Proteins; D016373:DNA, Antisense; D019012:Integrin beta1; D050799:STAT5 Transcription Factor; D051020:bcl-X Protein; D039942:Neuropilin-1; D003609:Dactinomycin; D011065:Poly(ADP-ribose) Polymerases; D053453:Caspase 9