Cyclooxygenase-2-Dependent Activation of Signal Transducer and Activator of Transcription 3 by Interleukin-6 in Non–Small Cell Lung Cancer

• Published in: Clinical cancer research 2005-11, Vol.11 (21), p.7674-7682
• Main Authors: DALWADI, Harnisha, KRYSAN, Kostyantyn, HEUZE-VOURC'H, Nathalie, DOHADWALA, Mariam, ELASHOFF, David, SHARMA, Sherven, CACALANO, Nicholas, LICHTENSTEIN, Alan, DUBINETT, Steven
• Format: Article
• Language: English
• Subjects: Amino Acid Motifs; and apoptosis resistance; Antineoplastic agents; Apoptosis; Biological and medical sciences; Blotting, Western; Carcinoma, Non-Small-Cell Lung - metabolism; Cell Differentiation; Cell Line, Tumor; Cell Survival; Cyclooxygenase 2 - biosynthesis; Cyclooxygenase 2 - physiology; Cyclooxygenase-2; Cytokines - metabolism; Enzyme Activation; Enzyme Inhibitors - pharmacology; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; interleukin-6; Interleukin-6 - metabolism; Lung Neoplasms - metabolism; Medical sciences; Neovascularization, Pathologic; non–small cell lung cancer; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Pneumology; RNA - metabolism; RNA, Small Interfering - metabolism; signal transducers and activators of transcription 3; Signal Transduction; STAT3 Transcription Factor - metabolism; Tumors of the respiratory system and mediastinum; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-05-1205

Purpose: Cyclooxygenase-2 (COX-2), phosphorylated signal transducers and activators of transcription 3 (STAT3), and interleukin-6 (IL-6) are elevated in non–small cell lung cancer (NSCLC). These molecules affect numerous cellular pathways, including angiogenesis and apoptosis resistance, and, therefore, may act in concert in NSCLC. Experimental Design: We examined IL-6 and phosphorylated STAT3 in COX-2-overexpressing [COX-2 sense-oriented (COX-2-S)] NSCLC cells and control cells. The effect of IL-6, STAT3, phosphatidylinositol 3-kinase, and mitogen-activated protein/extracellular signal-regulated kinase kinase on vascular endothelial growth factor (VEGF) production and apoptosis resistance was assessed in COX-2-overexpresing cells. Results: We report that NSCLC cells overexpressing COX-2 (COX-2-S) have increased IL-6 and phosphorylated STAT3 expression compared with control cells. IL-6 induced expression of VEGF in NSCLC cells. Moreover, blocking IL-6, mitogen-activated protein/extracellular signal-regulated kinase kinase, or phosphatidylinositol 3-kinase decreased VEGF production in COX-2-S cells. The addition of IL-6 to NSCLC cells resulted in increased apoptosis resistance. Furthermore, the inhibition of STAT3 or IL-6 induced apoptosis and reduced survivin expression, a member of the inhibitor of apoptosis protein family in COX-2-S cells. Conclusions: Overall, these findings suggest a novel pathway in which COX-2 activates STAT3 by inducing IL-6 expression. This pathway could contribute to tumor formation by promoting survivin-dependent apoptosis resistance and VEGF production. These findings provide a rationale for the future development of STAT3, IL-6, and/or COX-2-targeted therapies for the treatment of lung cancer.