Autocrine-mediated ErbB-2 kinase activation of STAT3 is required for growth factor independence of pancreatic cancer cell lines

Daniel T Dearmond, Michael G. Brattain, John Milburn Jessup, Jeffrey Kreisberg, Shazli Malik, Shujie Zhao, James W Freeman

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

Pancreatic ductal adenocarcinoma (PDAC) cell lines, MIA PaCa-2, and UK Pan-1, were used to investigate the role of ErbB2 in PDAC oncogenesis. Both these cell lines exhibit exogenous growth factor-independent proliferation that was attributed to the production of autocrine growth factors and/or overexpression of growth factor receptors. The exogenous growth factor-independent phenotype displayed by these PDAC cell lines was dependent on ErbB2 kinase activity since treatment of cells with tyrphostin AG879 prevented serum-free media (SFM) induction of cell proliferation. We determined that ErbB2 kinase contributed to aberrant cell cycle regulation in PDAC through the induction of cyclin D1 levels and the suppression of p21Cip1 and p27Kip1. Inhibition of ErbB2 kinase led to cell cycle arrest marked by an increased association of p27Kip1 with cdk2 and reduced levels of phosphorylated pRb. We further observed constitutive STAT3 activation in the PDAC cell lines and an increase in STAT3 activation upon stimulating quiescent cells with SFM. Inhibitors of ErbB2 kinase blocked STAT3 activation, whereas inhibition of EGFR kinase led to a slight reduction of STAT3 activation. STAT3 was coimmunoprev cipitated with ErbB2. SFM stimulation caused an increase in the association of ErbB2 and STAT3, which was blocked by inhibition of ErbB2 kinase. Expression of a STAT3 dominant negative prevented SFM-stimulated cell proliferation of MIA PaCa-2 cells, suggesting that activation of STAT3 by ErbB2 is required for a growth factor-independent phenotype of these cells. Consistent with this observation in PDAC cell lines, we found that most PDAC tumor specimens (10 of 11) showed constitutive activation of STAT3 and that ErbB2 was readily detected in most of these tumors (nine of 11). We believe that these findings indicate a novel mechanism of oncogenesis in PDAC and may suggest future therapeutic strategies in the treatment of PDAC.

Original languageEnglish (US)
Pages (from-to)7781-7795
Number of pages15
JournalOncogene
Volume22
Issue number49
DOIs
StatePublished - Oct 30 2003

Fingerprint

Pancreatic Neoplasms
Intercellular Signaling Peptides and Proteins
Adenocarcinoma
Phosphotransferases
Cell Line
Serum-Free Culture Media
Carcinogenesis
Cell Proliferation
Tyrphostins
Phenotype
Growth Factor Receptors
Cyclin D1
Cell Cycle Checkpoints
Neoplasms
Cell Cycle

Keywords

  • Cell signaling
  • ErbB-2
  • Growth factors
  • Pancreatic cancer

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Dearmond, D. T., Brattain, M. G., Jessup, J. M., Kreisberg, J., Malik, S., Zhao, S., & Freeman, J. W. (2003). Autocrine-mediated ErbB-2 kinase activation of STAT3 is required for growth factor independence of pancreatic cancer cell lines. Oncogene, 22(49), 7781-7795. https://doi.org/10.1038/sj.onc.1206966

Autocrine-mediated ErbB-2 kinase activation of STAT3 is required for growth factor independence of pancreatic cancer cell lines. / Dearmond, Daniel T; Brattain, Michael G.; Jessup, John Milburn; Kreisberg, Jeffrey; Malik, Shazli; Zhao, Shujie; Freeman, James W.

In: Oncogene, Vol. 22, No. 49, 30.10.2003, p. 7781-7795.

Research output: Contribution to journalArticle

Dearmond, DT, Brattain, MG, Jessup, JM, Kreisberg, J, Malik, S, Zhao, S & Freeman, JW 2003, 'Autocrine-mediated ErbB-2 kinase activation of STAT3 is required for growth factor independence of pancreatic cancer cell lines', Oncogene, vol. 22, no. 49, pp. 7781-7795. https://doi.org/10.1038/sj.onc.1206966
Dearmond, Daniel T ; Brattain, Michael G. ; Jessup, John Milburn ; Kreisberg, Jeffrey ; Malik, Shazli ; Zhao, Shujie ; Freeman, James W. / Autocrine-mediated ErbB-2 kinase activation of STAT3 is required for growth factor independence of pancreatic cancer cell lines. In: Oncogene. 2003 ; Vol. 22, No. 49. pp. 7781-7795.
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abstract = "Pancreatic ductal adenocarcinoma (PDAC) cell lines, MIA PaCa-2, and UK Pan-1, were used to investigate the role of ErbB2 in PDAC oncogenesis. Both these cell lines exhibit exogenous growth factor-independent proliferation that was attributed to the production of autocrine growth factors and/or overexpression of growth factor receptors. The exogenous growth factor-independent phenotype displayed by these PDAC cell lines was dependent on ErbB2 kinase activity since treatment of cells with tyrphostin AG879 prevented serum-free media (SFM) induction of cell proliferation. We determined that ErbB2 kinase contributed to aberrant cell cycle regulation in PDAC through the induction of cyclin D1 levels and the suppression of p21Cip1 and p27Kip1. Inhibition of ErbB2 kinase led to cell cycle arrest marked by an increased association of p27Kip1 with cdk2 and reduced levels of phosphorylated pRb. We further observed constitutive STAT3 activation in the PDAC cell lines and an increase in STAT3 activation upon stimulating quiescent cells with SFM. Inhibitors of ErbB2 kinase blocked STAT3 activation, whereas inhibition of EGFR kinase led to a slight reduction of STAT3 activation. STAT3 was coimmunoprev cipitated with ErbB2. SFM stimulation caused an increase in the association of ErbB2 and STAT3, which was blocked by inhibition of ErbB2 kinase. Expression of a STAT3 dominant negative prevented SFM-stimulated cell proliferation of MIA PaCa-2 cells, suggesting that activation of STAT3 by ErbB2 is required for a growth factor-independent phenotype of these cells. Consistent with this observation in PDAC cell lines, we found that most PDAC tumor specimens (10 of 11) showed constitutive activation of STAT3 and that ErbB2 was readily detected in most of these tumors (nine of 11). We believe that these findings indicate a novel mechanism of oncogenesis in PDAC and may suggest future therapeutic strategies in the treatment of PDAC.",
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