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Cyclic AMP-Responsive Element Binding Protein– and Nuclear Factor-B–Regulated CXC Chemokine Gene Expression in Lung Carcinogenesis

Authors' Affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Ja Seok Koo, Department of Thoracic/Head and Neck Medical Oncology, Unit 432, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-6363; Fax: 713-794-5997; E-mail: jskoo{at}mdanderson.org.

The recognition of the importance of angiogenesis in tumor progression has led to the development of antiangiogenesis as a new strategy for cancer treatment and prevention. By modulating tumor microenvironment and inducing angiogenesis, the proinflammatory cytokine interleukine (IL)-1β has been reported to promote tumor development. However, the factors mediating IL-1β–induced angiogenesis in non–small cell lung cancer (NSCLC) and the regulation of these angiogenic factors by IL-1β are less clear. Here, we report that IL-1β up-regulated an array of proangiogenic CXC chemokine genes in the NSCLC cell line A549 and in normal human tracheobronchial epithelium cells, as determined by microarray analysis. Further analysis revealed that IL-1β induced much higher protein levels of CXC chemokines in NSCLC cells than in normal human tracheobronchial epithelium cells. Conditioned medium from IL-1β–treated A549 cells markedly increased endothelial cell migration, which was suppressed by neutralizing antibodies against CXCL5 and CXCR2. We also found that IL-1β–induced CXC chemokine gene overexpression in NSCLC cells was abrogated with the knockdown of cyclic AMP-responsive element binding protein (CREB) or nuclear factor B (NF-B). Moreover, the expression of the CXC chemokine genes as well as CREB and NF-B activities was greatly increased in the tumorigenic NSCLC cell line compared with normal, premalignant immortalized or nontumorigenic cell lines. A disruptor of the interaction between CREB-binding protein and transcription factors such as CREB and NF-B, 2-naphthol-AS-E-phosphate (KG-501), inhibited IL-1β–induced CXC chemokine gene expression and angiogenic activity in NSCLC. We propose that targeting CREB or NF-B using small-molecule inhibitors, such as KG-501, holds promise as a preventive and/or therapeutic approach for NSCLC.

Key Words: Angiogenesis • chemoprevention • CREB • NF-B • CXC Chemokine • lung cancer

Commentary

Out of the Shadows: CXC Chemokines in Promoting Aberrant Lung Cancer Angiogenesis

Robert M. Strieter
Cancer Prevention Research 2008 1: 305-307. [Full Text] [PDF]