Multiple mitogenic pathways in pancreatic cancer cells are blocked by a truncated epidermal growth factor receptor

Kei Matsuda, Takenao Idezawa, Xue Juan You, Nayantara H. Kothari, Hung Fan, Murray Korc

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

The epidermal growth factor (EGF) receptor (EGFR) family consists of four transmembrane tyrosine kinases that undergo homodimerization and heterodimerization. Pancreatic cancers overexpress these receptors. To examine the effects of EGFR blockade on pancreatic cancer cell mitogenesis in relation to activation of specific signaling pathways, four pancreatic cancer cell lines were infected with an adenoviral vector encoding a truncated EGFR (AdtrEGFR), and activation of signaling was assessed with the mitogen-activated protein kinase (MAPK) kinase inhibitors PD98059 and U0126, the p38 MAPK inhibitor SB203580, and the c-Jun NH2-terminal kinase inhibitor SP600125. In all four cell lines, AdtrEGFR markedly attenuated EGF and heparin-binding EGF-dependent cell growth, EGFR family tyrosine phosphorylation, and phosphorylation of MAPK, c-Jun NH2-terminal kinase, p38 MAPK, and activating transcription factor 2. AdtrEGFR did not alter fibroblast growth factor 2 actions on mitogenesis. In ASPC-1, PANC-1, and T3M4 cells, PD98059 and U0126 inhibited MAPK kinase activation but not EGF-stimulated mitogenesis, whereas SB203580 inhibited EGF-stimulated mitogenesis, p38 MAPK activation, and MAPK-activated protein kinase 2 activation, without attenuating the mitogenic effect of insulin-like growth factor 1. In contrast, in COLO-357 cells, PD98059, and U0126, but not SB203580, inhibited EGF-stimulated mitogenesis, whereas SP600125 did not alter the mitogenic actions of EGF in any of the cell lines. Thus, EGF promotes proliferation via the MAPK in COLO-357 cells but via p38 MAPK in ASPC-1, PANC-1, and T3M4 cells, and whereas EGFR activation leads to the activation of all four members of the EGFR family in these cells, downstream signaling is efficiently blocked by AdtrEGFR.

Original languageEnglish (US)
Pages (from-to)5611-5617
Number of pages7
JournalCancer Research
Volume62
Issue number19
StatePublished - Oct 1 2002
Externally publishedYes

Fingerprint

Pancreatic Neoplasms
Epidermal Growth Factor Receptor
Epidermal Growth Factor
p38 Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinases
JNK Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinase Kinases
Cell Line
Activating Transcription Factor 2
Phosphorylation
Somatomedins
Fibroblast Growth Factor 2
Protein Kinase Inhibitors
Protein-Tyrosine Kinases
Protein Kinases
Tyrosine
Heparin
Growth
U 0126
SB 203580

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Matsuda, K., Idezawa, T., You, X. J., Kothari, N. H., Fan, H., & Korc, M. (2002). Multiple mitogenic pathways in pancreatic cancer cells are blocked by a truncated epidermal growth factor receptor. Cancer Research, 62(19), 5611-5617.

Multiple mitogenic pathways in pancreatic cancer cells are blocked by a truncated epidermal growth factor receptor. / Matsuda, Kei; Idezawa, Takenao; You, Xue Juan; Kothari, Nayantara H.; Fan, Hung; Korc, Murray.

In: Cancer Research, Vol. 62, No. 19, 01.10.2002, p. 5611-5617.

Research output: Contribution to journalArticle

Matsuda, K, Idezawa, T, You, XJ, Kothari, NH, Fan, H & Korc, M 2002, 'Multiple mitogenic pathways in pancreatic cancer cells are blocked by a truncated epidermal growth factor receptor', Cancer Research, vol. 62, no. 19, pp. 5611-5617.
Matsuda K, Idezawa T, You XJ, Kothari NH, Fan H, Korc M. Multiple mitogenic pathways in pancreatic cancer cells are blocked by a truncated epidermal growth factor receptor. Cancer Research. 2002 Oct 1;62(19):5611-5617.
Matsuda, Kei ; Idezawa, Takenao ; You, Xue Juan ; Kothari, Nayantara H. ; Fan, Hung ; Korc, Murray. / Multiple mitogenic pathways in pancreatic cancer cells are blocked by a truncated epidermal growth factor receptor. In: Cancer Research. 2002 ; Vol. 62, No. 19. pp. 5611-5617.
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