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Activation of Stat3 by receptor tyrosine kinases and cytokines regulates survival in human non-small cell carcinoma cells

Oncogene volume 22, pages 4150–4165 (2003)Cite this article

Abstract

Overexpression of receptor tyrosine kinases including the epidermal growth factor receptor (EGF-R) as well as nonreceptor tyrosine kinases, such as Src, have been implicated in the formation of human lung cancers. In addition, cytokines like interleukin-6 (IL-6) have been demonstrated to modulate lung cancer cell growth and elevated levels of IL-6 have been shown to be an adverse prognostic factor for patients with lung cancer. Despite a large body of evidence pointing to their potential importance, few direct studies into the role of signal transducers and activators of transcription (STAT) pathways in human lung cancer have been undertaken. Here we demonstrate that multiple nonsmall cell lung cancer cell lines demonstrate constitutive Stat3 DNA-binding activity. Stat3 DNA-binding activity is specifically upregulated by the addition of epidermal growth factor (EGF), IL-6, and hepatocyte-derived growth factor (HGF). Furthermore, the stimulation of Stat3 DNA-binding activity by EGF requires the activity of EGF-R tyrosine kinase as well as Src-kinase, while the upregulation of Stat3 activity by IL-6 or HGF requires only Src-kinase activity. Treatment of A549 lung cancer cells with PD180970 or SU6656, both pharmacological inhibitors of Src-kinase, resulted in reduced Src and Stat3 activity, cell cycle arrest in G2, and reduced viability of cells accompanied by induction of apoptosis. Treatment of Stat3-positive A549 and H358 cells with antisense Stat3 oligonucleotides results in complete loss of Stat3 DNA-binding activity and apoptosis, while Stat3-positive H1299 cells remained healthy. Finally, an adenoviral vector expressing a dominant-negative Stat3 isoform results in loss of Stat3 DNA-binding activity, apoptosis, and reduced cellular viability. These results demonstrate a role of Stat3 in transducing survival signals downstream of tyrosine kinases such as Src, EGF-R, and c-Met, as well as cytokines such as IL-6, in human nonsmall cell lung cancers.

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Acknowledgements

We thank members of the Jove lab for stimulating discussions and help with experiments, Dr Doug Cress for advice, Dr Gerold Bepler for providing cell lines, Rebecca Alexander for administrative assistance, Dr Martin Broome at SUGEN for providing SU6656, and the Moffitt Cancer Center Flow Cytometry and Molecular Imaging Core Facilities. This work was partially funded by the Chiles Endowment Biomedical Research Program of the Florida Department of Health (EBH) and by NIH grant CA82533 (RJ).

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Authors and Affiliations

  1. Experimental Therapeutics, H. Lee Moffitt Cancer Center and Research Insitute, University of South Florida College of Medicine Tampa, 33612, FL, USA

    Lanxi Song & Eric B Haura

  2. Molecular Oncology Programs, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida College of Medicine Tampa, 33612, FL, USA

    James Turkson & Richard Jove

  3. Department of Interdisciplinary Oncology, University of South Florida College of Medicine, Tampa, 33612, FL, USA

    Lanxi Song, James Turkson, Richard Jove & Eric B Haura

  4. Isis Pharmaceuticals, Carlsbad, CA, USA

    James G Karras

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  1. Lanxi Song
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Correspondence to Eric B Haura.

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Song, L., Turkson, J., Karras, J. et al. Activation of Stat3 by receptor tyrosine kinases and cytokines regulates survival in human non-small cell carcinoma cells. Oncogene 22, 4150–4165 (2003). https://doi.org/10.1038/sj.onc.1206479

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