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

Kuo Ting Chang, Chun Ming Tsai, Yih Chy Chiou, Chao Hua Chiu, King Song Jeng, Chi Ying F. Huang

Research output: Contribution to journalArticlepeer-review

58 Citations (Scopus)

Abstract

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 STATSY705F (a dominant-negative STATS) 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 p3S 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.

Original languageEnglish
Pages (from-to)L446-L453
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume289
Issue number3 33-3
DOIs
Publication statusPublished - Sept 2005
Externally publishedYes

Keywords

  • Neuron-specific enolase
  • p38 mitogen-activated protein kinase
  • Signal transducer and activator of transcription

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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