Reciprocal regulation of c-Src and STAT3 in non-small cell lung cancer

Lauren Averett Byers, Banibrata Sen, Babita Saigal, Lixia Diao, Jing Wang, Meera Nanjundan, Tina Cascone, Gordon B. Mills, John V. Heymach, Faye M. Johnson

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    73 Scopus citations

    Abstract

    Purpose: Signal transducer and activator of transcription-3 (STAT3) is downstream of growth factor and cytokine receptors, and regulates key oncogenic pathways in non-small cell lung cancer (NSCLC). Activation of STAT3 by cellular Src (c-Src) promotes tumor progression. We hypothesized that c-Src inhibition could activate STAT3 by inducing a homeostatic feedback loop, contributing to c-Src inhibitor resistance. Experimental Design: The effects of c-Src inhibition on total and phosphorylated STAT3 were measured in NSCLC cell lines and in murine xenograft models by Western blotting. c-Src and STAT3 activity as indicated by phosphorylation was determined in 46 human tumors and paired normal lung by reverse phase protein array. Modulation of dasatinib (c-Src inhibitor) cytotoxicity by STAT3 knockdown was measured by MTT, cell cycle, and apoptosis assays. Results: Depletion of c-Src by small interfering RNA or sustained inhibition by dasatinib increased pSTAT3, which could be blocked by inhibition of JAK. Similarly, in vivo pSTAT3 levels initially decreased but were strongly induced after sustained dasatinib treatment. In human tumors, phosphorylation of the autoinhibitory site of c-Src (Y527) correlated with STAT3 phosphorylation (r = 0.64; P = 2.5 x 10-6). STAT3 knockdown enhanced the cytotoxicity of dasatinib. Conclusions: c-Src inhibition leads to JAK-dependent STAT3 activation in vitro and in vivo. STAT3 knockdown enhances the cytotoxicity of dasatinib, suggesting a compensatory pathway that allows NSCLC survival. Data from human tumors showed a reciprocal regulation of c-Src and STAT3 activation, suggesting that this compensatory pathway functions in human NSCLC. These results provide a rationale for combining c-Src and STAT3 inhibition to improve clinical responses.

    Original languageEnglish (US)
    Pages (from-to)6852-6861
    Number of pages10
    JournalClinical Cancer Research
    Volume15
    Issue number22
    DOIs
    StatePublished - Nov 15 2009

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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    Byers, L. A., Sen, B., Saigal, B., Diao, L., Wang, J., Nanjundan, M., Cascone, T., Mills, G. B., Heymach, J. V., & Johnson, F. M. (2009). Reciprocal regulation of c-Src and STAT3 in non-small cell lung cancer. Clinical Cancer Research, 15(22), 6852-6861. https://doi.org/10.1158/1078-0432.CCR-09-0767