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

Oncogene volume 22, pages 7781–7795 (2003)Cite this article

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 coimmunoprecipitated 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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Acknowledgements

This work was supported by a San Antonio Cancer Institute Core Grant P30 CA 54174 and by NIH-RO1 Grant CA69122 to JWF. We thank Dr Richard Jove, Moffitt Cancer Center at the University of South Florida, Tampa, FL, for providing us with the STAT3β construct and for helpful discussion regarding the use of this construct.

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Authors and Affiliations

  1. Department of Surgery, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, 78229-3900, TX, USA

    Daniel DeArmond, Jeffrey Kreisberg, Shazli Malik & James W Freeman

  2. Research and Development, Audie Murphy Veterans Administration Hospital, San Antonio, 78229, TX, USA

    Jeffrey Kreisberg & Shazli Malik

  3. Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA

    Michael G Brattain

  4. Department of Surgery, Georgetown University Medical Center, Washington, 20007, DC, USA

    John Milburn Jessup

  5. Department of Medicine, Division of Medical Oncology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, 78229-3900, TX, USA

    Shujie Zhao & James W Freeman

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  1. Daniel DeArmond
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Correspondence to James W Freeman.

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DeArmond, D., Brattain, M., Jessup, J. et al. Autocrine-mediated ErbB-2 kinase activation of STAT3 is required for growth factor independence of pancreatic cancer cell lines. Oncogene 22, 7781–7795 (2003). https://doi.org/10.1038/sj.onc.1206966

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