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This Article Full Text Full Text (PDF) All Versions of this Article: 289/3/L446    most recent 00089.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Chang, K.-T. Articles by Huang, C.-Y. F. Search for Related Content PubMed PubMed Citation Articles by Chang, K.-T. Articles by Huang, C.-Y. F.

IL-6 induces neuroendocrine dedifferentiation and cell proliferation in non-small cell lung cancer cells

¹Graduate Institute of Life Sciences, National Defense Medical Center, Taipei; ²Division of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli County; ³Section of Thoracic Oncology, Chest Department, Taipei Veterans General Hospital, and Department of Medicine, School of Medicine, National Yang-Ming University, Taipei; ⁴Institute of Molecular Biology, Academia Sinica, Nankang, Taipei; ⁵Institute of Biotechnology in Medicine, National Yang-Ming University, Taipei; and ⁶Department of Computer Science and Information Engineering, National Taiwan University, Taipei, Taiwan

Submitted 28 February 2005 ; accepted in final form 9 May 2005

Interleukin-6 (IL-6) has been identified as an important growth regulator of lung cancer cells. Elevation of serum levels of IL-6 has been found in a subpopulation of lung cancer patients, but rarely in patients with benign lung diseases. Approximately 15% of non-small cell lung cancer (NSCLC) tumors exhibit neuroendocrine (NE) properties (NSCLC-NE) and have been suggested to have the biological characteristics similar to small cell lung cancer (SCLC) with early metastasis and initial responsiveness to chemotherapy. We recently showed that IL-6 promotes cell proliferation and downregulates the expression of neuron-specific enolase (NSE, one of the major NE markers) in NSCLC-NE cells. In this study, we show that IL-6 stimulates a transient increase of tyrosine phosphorylation of STAT3 in a dose-dependent fashion. Inhibition of STAT3 signaling pathway by either AG-490 (JAK2-specific inhibitor) or overexpression of STAT3Y705F (a dominant-negative STAT3) reverses NSE expression in IL-6- treated NSCLC-NE cells. In addition, IL-6 induces phosphorylation and activation of p38 MAPK. SB-203580, a p38 MAPK-specific inhibitor, inhibits IL-6-induced p38 MAPK phosphorylating activity and suppresses IL-6-stimulated cell proliferation. Together, our results indicate that STAT3 signaling pathway is involved in IL-6-induced NE differentiation and that p38 MAPK is associated with IL-6-stimulated growth regulation in NSCLC-NE cells. These data suggest that both kinase pathways play critical roles in the pathogenesis of NSCLC-NE malignancies, providing new molecular targets for future therapeutic approaches.

neuron-specific enolase; signal transducer and activator of transcription; p38 mitogen-activated protein kinase

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