Signal transducer and activator of transcription 3 as molecular therapy for non-small-cell lung cancer

Cheng Yi Wang, Ting Ting Chao, Wei Tien Tai, Fang Yu Chang, Wen Pin Su, Yen Lin Chen, Pao Tzu Chen, Ching Yu Weng, Ang Yuan, Chung Wai Shiau, Chong Jen Yu, Kuen Feng Chen

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9 Citations (Scopus)

Abstract

Introduction: Targeting signal transducer and activator of transcription 3 (STAT3), a transcription factor that modulates survival-directed transcription, is often persistently activated in epidermal growth factor receptor (EGFR) wild-type non-small-cell lung cancer (NSCLC). The aim of this study was to determine whether sorafenib and its derivative can inhibit EGFR wild-type NSCLC via STAT3 inactivation. Methods: EGFR wild-type NSCLC cell lines (A549 H292 H322 H358 and H460) were treated with sorafenib or SC-1, a sorafenib derivative that closely resembled sorafenib structurally but was devoid of kinase inhibitory activity. Apoptosis and signal transduction were analyzed. In vivo efficacy was determined in nude mice with H460 and A549 xenograft. Results: SC-1 had better effects than sorafenib on growth inhibition and apoptosis in all tested EGFR wild-type NSCLC lines. SC-1 reduced STAT3 phosphorylation at tyrosine 705 in all tested EGFR wild-type NSCLC cells. The expression of STAT3-driven genes, including cylcin D1 and survivin, was also repressed by SC-1. Ectopic expression of STAT3 in H460 cells abolished apoptosis in SC-1-treated cells. Sorafenib and SC-1 enhanced Src homology-2 containing protein tyrosine phosphatase-1 (SHP-1) activity, whereas knockdown of SHP-1, but not SHP-2 or protein-tyrosine phosphatase 1B (PTP-1B), by small interference RNA reduced SC-1-induced apoptosis. SC-1 significantly reduced H460 and A549 tumor growth in vivo through SHP-1/STAT3 pathway. Conclusions: SC-1 provides proof that targeting STAT3 signaling pathway may be a novel approach for the treatment of EGFR wild-type NSCLC.

Original languageEnglish
Pages (from-to)488-496
Number of pages9
JournalJournal of Thoracic Oncology
Volume9
Issue number4
DOIs
Publication statusPublished - 2014 Apr

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pulmonary and Respiratory Medicine

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    Wang, C. Y., Chao, T. T., Tai, W. T., Chang, F. Y., Su, W. P., Chen, Y. L., Chen, P. T., Weng, C. Y., Yuan, A., Shiau, C. W., Yu, C. J., & Chen, K. F. (2014). Signal transducer and activator of transcription 3 as molecular therapy for non-small-cell lung cancer. Journal of Thoracic Oncology, 9(4), 488-496. https://doi.org/10.1097/JTO.0000000000000107