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

Research output: Contribution to journalArticle

7 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 1

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STAT3 Transcription Factor
Non-Small Cell Lung Carcinoma
Epidermal Growth Factor Receptor
Apoptosis
Therapeutics
Non-Receptor Type 11 Protein Tyrosine Phosphatase
Non-Receptor Type 6 Protein Tyrosine Phosphatase
Non-Receptor Type 1 Protein Tyrosine Phosphatase
Growth
RNA Interference
Heterografts
Nude Mice
Tyrosine
sorafenib
Signal Transduction
Transcription Factors
Phosphotransferases
Phosphorylation
Genes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

Wang, Cheng Yi ; Chao, Ting Ting ; Tai, Wei Tien ; Chang, Fang Yu ; Su, Wen-Pin ; Chen, Yen Lin ; Chen, Pao Tzu ; Weng, Ching Yu ; Yuan, Ang ; Shiau, Chung Wai ; Yu, Chong Jen ; Chen, Kuen Feng. / Signal transducer and activator of transcription 3 as molecular therapy for non-small-cell lung cancer. In: Journal of Thoracic Oncology. 2014 ; Vol. 9, No. 4. pp. 488-496.
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title = "Signal transducer and activator of transcription 3 as molecular therapy for non-small-cell lung cancer",
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.",
author = "Wang, {Cheng Yi} and Chao, {Ting Ting} and Tai, {Wei Tien} and Chang, {Fang Yu} and Wen-Pin Su and Chen, {Yen Lin} and Chen, {Pao Tzu} and Weng, {Ching Yu} and Ang Yuan and Shiau, {Chung Wai} and Yu, {Chong Jen} and Chen, {Kuen Feng}",
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Wang, CY, Chao, TT, Tai, WT, Chang, FY, Su, W-P, Chen, YL, Chen, PT, Weng, CY, Yuan, A, Shiau, CW, Yu, CJ & Chen, KF 2014, 'Signal transducer and activator of transcription 3 as molecular therapy for non-small-cell lung cancer', Journal of Thoracic Oncology, vol. 9, no. 4, pp. 488-496. https://doi.org/10.1097/JTO.0000000000000107

Signal transducer and activator of transcription 3 as molecular therapy for non-small-cell lung cancer. / Wang, Cheng Yi; Chao, Ting Ting; Tai, Wei Tien; Chang, Fang Yu; Su, Wen-Pin; Chen, Yen Lin; Chen, Pao Tzu; Weng, Ching Yu; Yuan, Ang; Shiau, Chung Wai; Yu, Chong Jen; Chen, Kuen Feng.

In: Journal of Thoracic Oncology, Vol. 9, No. 4, 01.04.2014, p. 488-496.

Research output: Contribution to journalArticle

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T1 - Signal transducer and activator of transcription 3 as molecular therapy for non-small-cell lung cancer

AU - Wang, Cheng Yi

AU - Chao, Ting Ting

AU - Tai, Wei Tien

AU - Chang, Fang Yu

AU - Su, Wen-Pin

AU - Chen, Yen Lin

AU - Chen, Pao Tzu

AU - Weng, Ching Yu

AU - Yuan, Ang

AU - Shiau, Chung Wai

AU - Yu, Chong Jen

AU - Chen, Kuen Feng

PY - 2014/4/1

Y1 - 2014/4/1

N2 - 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.

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