Hepatocyte growth factor-mediated cell invasion in pancreatic cancer cells is dependent on neuropilin-1

Arikira Matsushita, Tobias Götze, Murray Korc

Research output: Contribution to journalArticle

92 Citations (Scopus)

Abstract

Neuropilin-1 (Np-1), a receptor for semaphorin 3A and vascular endothelial growth factor, is expressed at high levels in pancreatic ductal adenocarcinoma (PDAC). To assess the potential role of Np-1 in PDAC, COLO-357 pancreatic cancer cells, which express relatively low levels of Np-1, were stably transfected with the Np-1 cDNA. Np-1 overexpression was associated with enhanced cell invasiveness in response to hepatocyte growth factor (HGF), and this effect was abolished by small interfering RNA-mediated down-regulation of c-Met. Conversely, in PANC-1 pancreatic cancer cells, which express relatively high levels of Np-1, suppression of endogenous Np-1 completely abolished HGF-mediated cell invasion. To determine which pathways are involved in Np-1-mediated facilitation of c-Met-dependent cell invasiveness, the effects of HGF on signaling were examined next in sham-transfected and Np-1-overexpressing COLO-357 cells. HGF actions on c-Met tyrosine phosphorylation and p38 mitogen-activated protein kinase (MAPK) activation were increased in Np-1-overexpressing COLO-357 cells by comparison with HGF effects in sham-transfected cells. SB203580, an inhibitor of p38 MAPK, suppressed HGF-induced invasion in Np-1-overexpressing cells, whereas U0126, a MAP/extracellular signal-regulated kinase kinase inhibitor, was without effect. PP2, a Src inhibitor, and LY294002, a phosphatidylinositol 3-kinase inhibitor, also suppressed HGF-induced invasion in these cells. Immunoprecipitation studies revealed that Np-1 associated with c-Met, but not with epidermal growth factor receptor, family members. Confocal microscopy indicated that this association occurred on the plasma membrane and that HGF promoted the internalization of Np-1-c-Met complex, leading to its perinuclear localization. These findings indicate that Np-1 is required for efficient activation of c-Met-dependent pathways that promote cell invasiveness.

Original languageEnglish (US)
Pages (from-to)10309-10316
Number of pages8
JournalCancer Research
Volume67
Issue number21
DOIs
StatePublished - Nov 1 2007
Externally publishedYes

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Neuropilin-1
Hepatocyte Growth Factor
Pancreatic Neoplasms
p38 Mitogen-Activated Protein Kinases
Adenocarcinoma
Semaphorin-3A
Phosphatidylinositol 3-Kinase
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Extracellular Signal-Regulated MAP Kinases

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Hepatocyte growth factor-mediated cell invasion in pancreatic cancer cells is dependent on neuropilin-1. / Matsushita, Arikira; Götze, Tobias; Korc, Murray.

In: Cancer Research, Vol. 67, No. 21, 01.11.2007, p. 10309-10316.

Research output: Contribution to journalArticle

Matsushita, Arikira ; Götze, Tobias ; Korc, Murray. / Hepatocyte growth factor-mediated cell invasion in pancreatic cancer cells is dependent on neuropilin-1. In: Cancer Research. 2007 ; Vol. 67, No. 21. pp. 10309-10316.
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abstract = "Neuropilin-1 (Np-1), a receptor for semaphorin 3A and vascular endothelial growth factor, is expressed at high levels in pancreatic ductal adenocarcinoma (PDAC). To assess the potential role of Np-1 in PDAC, COLO-357 pancreatic cancer cells, which express relatively low levels of Np-1, were stably transfected with the Np-1 cDNA. Np-1 overexpression was associated with enhanced cell invasiveness in response to hepatocyte growth factor (HGF), and this effect was abolished by small interfering RNA-mediated down-regulation of c-Met. Conversely, in PANC-1 pancreatic cancer cells, which express relatively high levels of Np-1, suppression of endogenous Np-1 completely abolished HGF-mediated cell invasion. To determine which pathways are involved in Np-1-mediated facilitation of c-Met-dependent cell invasiveness, the effects of HGF on signaling were examined next in sham-transfected and Np-1-overexpressing COLO-357 cells. HGF actions on c-Met tyrosine phosphorylation and p38 mitogen-activated protein kinase (MAPK) activation were increased in Np-1-overexpressing COLO-357 cells by comparison with HGF effects in sham-transfected cells. SB203580, an inhibitor of p38 MAPK, suppressed HGF-induced invasion in Np-1-overexpressing cells, whereas U0126, a MAP/extracellular signal-regulated kinase kinase inhibitor, was without effect. PP2, a Src inhibitor, and LY294002, a phosphatidylinositol 3-kinase inhibitor, also suppressed HGF-induced invasion in these cells. Immunoprecipitation studies revealed that Np-1 associated with c-Met, but not with epidermal growth factor receptor, family members. Confocal microscopy indicated that this association occurred on the plasma membrane and that HGF promoted the internalization of Np-1-c-Met complex, leading to its perinuclear localization. These findings indicate that Np-1 is required for efficient activation of c-Met-dependent pathways that promote cell invasiveness.",
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