Reciprocal Regulation of c-Src and STAT3 in Non-Small Cell Lung Cancer
- 11 November 2009
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 15 (22), 6852-6861
- https://doi.org/10.1158/1078-0432.ccr-09-0767
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 × 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. (Clin Cancer Res 2009;15(22):6852–61)Keywords
This publication has 48 references indexed in Scilit:
- The Src Inhibitor AZD0530 Blocks Invasion and May Act as a Radiosensitizer in Lung Cancer CellsJournal of Thoracic Oncology, 2009
- Sustained Src Inhibition Results in Signal Transducer and Activator of Transcription 3 (STAT3) Activation and Cancer Cell Survival via Altered Janus-Activated Kinase–STAT3 BindingCancer Research, 2009
- Lestaurtinib (CEP701) is a JAK2 inhibitor that suppresses JAK2/STAT5 signaling and the proliferation of primary erythroid cells from patients with myeloproliferative disordersBlood, 2008
- Efficacy of TG101348, a Selective JAK2 Inhibitor, in Treatment of a Murine Model of JAK2V617F-Induced Polycythemia VeraCancer Cell, 2008
- Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitorsNature Biotechnology, 2007
- MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 SignalingScience, 2007
- Src-Family Kinases Are Activated in Non-Small Cell Lung Cancer and Promote the Survival of Epidermal Growth Factor Receptor-Dependent Cell LinesThe American Journal of Pathology, 2007
- KRAS Mutations and Primary Resistance of Lung Adenocarcinomas to Gefitinib or ErlotinibPLoS Medicine, 2005
- The STATs of cancer — new molecular targets come of ageNature Reviews Cancer, 2004
- Src kinase contributes to the metastatic spread of carcinoma cellsOncogene, 2002