Cooperative interaction between protein inhibitor of activated signal transducer and activator of transcription-3 with epidermal growth factor receptor blockade in lung cancer

Amy Kluge, Snehal Dabir, Jeffrey Kern, David Nethery, Balazs Halmos, Patrick Chi-Chung Ma, Afshin Dowlati

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Epidermal Growth Factor Receptor (EGFR) targeting in non-small cell lung cancer (NSCLC) is an established treatment modality; however, it only benefits a minority of patients. STAT3 (signal transducer and activator of transcription-3) plays an important role in the oncogenic signal transduction pathway of NSCLC. Inhibition of STAT3 results in NSCLC growth inhibition and apoptosis. We have previously shown that combined inhibition of EGFR and STAT3 by small molecules resulted in improved therapeutic efficacy as compared with blocking EGFR alone. However, the STAT3 protein has a number of endogenous negative regulators including PIAS3 (Protein Inhibitor of Activated STAT3). In this study, we investigated for the first time the role of PIAS3 in modulating oncogenic EGFR-STAT3 signaling pathway in lung cancer and the anti-proliferative effect of using PIAS3 in conjunction with EGFR blockade in NSCLC. We demonstrate that PIAS3 is expressed in variable degrees in all NSCLC cells. EGF and IL-6 stimulation resulted in the association of PIAS3 with STAT3. The PIAS3/STAT3 complex then bound the STAT3 DNA binding sequence resulting in STAT3 regulated gene expression. Over-expression of PIAS3, using a PIAS3 expression construct, decreases STAT3 transcriptional activity. Furthermore, over-expression of PIAS3 consistently decreased proliferation. EGFR blockade and PIAS3 over-expression in combination had significantly greater anti-proliferative effects as compared with either EGFR blockade or PIAS3 over-expression alone. In conclusion, PIAS3 is expressed in NSCLC cell lines and its over-expression decreased STAT3 transcriptional activity, decreased proliferation of NSCLC cells and when used in conjunction with EGFR inhibitors, increased the anti-proliferative effects.

Original languageEnglish (US)
Pages (from-to)1728-1734
Number of pages7
JournalInternational Journal of Cancer
Volume125
Issue number7
DOIs
StatePublished - Oct 1 2009

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STAT3 Transcription Factor
Epidermal Growth Factor Receptor
Lung Neoplasms
Non-Small Cell Lung Carcinoma
Proteins
STAT Transcription Factors
Epidermal Growth Factor
Interleukin-6
Signal Transduction

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

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title = "Cooperative interaction between protein inhibitor of activated signal transducer and activator of transcription-3 with epidermal growth factor receptor blockade in lung cancer",
abstract = "Epidermal Growth Factor Receptor (EGFR) targeting in non-small cell lung cancer (NSCLC) is an established treatment modality; however, it only benefits a minority of patients. STAT3 (signal transducer and activator of transcription-3) plays an important role in the oncogenic signal transduction pathway of NSCLC. Inhibition of STAT3 results in NSCLC growth inhibition and apoptosis. We have previously shown that combined inhibition of EGFR and STAT3 by small molecules resulted in improved therapeutic efficacy as compared with blocking EGFR alone. However, the STAT3 protein has a number of endogenous negative regulators including PIAS3 (Protein Inhibitor of Activated STAT3). In this study, we investigated for the first time the role of PIAS3 in modulating oncogenic EGFR-STAT3 signaling pathway in lung cancer and the anti-proliferative effect of using PIAS3 in conjunction with EGFR blockade in NSCLC. We demonstrate that PIAS3 is expressed in variable degrees in all NSCLC cells. EGF and IL-6 stimulation resulted in the association of PIAS3 with STAT3. The PIAS3/STAT3 complex then bound the STAT3 DNA binding sequence resulting in STAT3 regulated gene expression. Over-expression of PIAS3, using a PIAS3 expression construct, decreases STAT3 transcriptional activity. Furthermore, over-expression of PIAS3 consistently decreased proliferation. EGFR blockade and PIAS3 over-expression in combination had significantly greater anti-proliferative effects as compared with either EGFR blockade or PIAS3 over-expression alone. In conclusion, PIAS3 is expressed in NSCLC cell lines and its over-expression decreased STAT3 transcriptional activity, decreased proliferation of NSCLC cells and when used in conjunction with EGFR inhibitors, increased the anti-proliferative effects.",
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Cooperative interaction between protein inhibitor of activated signal transducer and activator of transcription-3 with epidermal growth factor receptor blockade in lung cancer. / Kluge, Amy; Dabir, Snehal; Kern, Jeffrey; Nethery, David; Halmos, Balazs; Ma, Patrick Chi-Chung; Dowlati, Afshin.

In: International Journal of Cancer, Vol. 125, No. 7, 01.10.2009, p. 1728-1734.

Research output: Contribution to journalArticle

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T1 - Cooperative interaction between protein inhibitor of activated signal transducer and activator of transcription-3 with epidermal growth factor receptor blockade in lung cancer

AU - Kluge, Amy

AU - Dabir, Snehal

AU - Kern, Jeffrey

AU - Nethery, David

AU - Halmos, Balazs

AU - Ma, Patrick Chi-Chung

AU - Dowlati, Afshin

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AB - Epidermal Growth Factor Receptor (EGFR) targeting in non-small cell lung cancer (NSCLC) is an established treatment modality; however, it only benefits a minority of patients. STAT3 (signal transducer and activator of transcription-3) plays an important role in the oncogenic signal transduction pathway of NSCLC. Inhibition of STAT3 results in NSCLC growth inhibition and apoptosis. We have previously shown that combined inhibition of EGFR and STAT3 by small molecules resulted in improved therapeutic efficacy as compared with blocking EGFR alone. However, the STAT3 protein has a number of endogenous negative regulators including PIAS3 (Protein Inhibitor of Activated STAT3). In this study, we investigated for the first time the role of PIAS3 in modulating oncogenic EGFR-STAT3 signaling pathway in lung cancer and the anti-proliferative effect of using PIAS3 in conjunction with EGFR blockade in NSCLC. We demonstrate that PIAS3 is expressed in variable degrees in all NSCLC cells. EGF and IL-6 stimulation resulted in the association of PIAS3 with STAT3. The PIAS3/STAT3 complex then bound the STAT3 DNA binding sequence resulting in STAT3 regulated gene expression. Over-expression of PIAS3, using a PIAS3 expression construct, decreases STAT3 transcriptional activity. Furthermore, over-expression of PIAS3 consistently decreased proliferation. EGFR blockade and PIAS3 over-expression in combination had significantly greater anti-proliferative effects as compared with either EGFR blockade or PIAS3 over-expression alone. In conclusion, PIAS3 is expressed in NSCLC cell lines and its over-expression decreased STAT3 transcriptional activity, decreased proliferation of NSCLC cells and when used in conjunction with EGFR inhibitors, increased the anti-proliferative effects.

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