Cyclic AMP-Responsive Element Binding Protein– and Nuclear Factor-κB–Regulated CXC Chemokine Gene Expression in Lung Carcinogenesis
Open Access
- 1 October 2008
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Prevention Research
- Vol. 1 (5), 316-328
- https://doi.org/10.1158/1940-6207.capr-07-0002
Abstract
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 κB (NF-κB). Moreover, the expression of the CXC chemokine genes as well as CREB and NF-κB 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-κB, 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-κB using small-molecule inhibitors, such as KG-501, holds promise as a preventive and/or therapeutic approach for NSCLC.Other Versions
This publication has 65 references indexed in Scilit:
- Cyclic AMP Response Element-Binding Protein Overexpression: A Feature Associated with Negative Prognosis in Never Smokers with Non–Small Cell Lung CancerCancer Research, 2008
- Growth Suppression of Lung Cancer Cells by Targeting Cyclic AMP Response Element-Binding ProteinCancer Research, 2008
- Cancer Statistics, 2008CA: A Cancer Journal for Clinicians, 2008
- Proteomics-Based Identification of Proteins Secreted in Apical Surface Fluid of Squamous Metaplastic Human Tracheobronchial Epithelial Cells Cultured by Three-Dimensional Organotypic Air-Liquid Interface MethodCancer Research, 2007
- Polymorphisms of TNFα, IL1β, and IL1RN genes in chronic obstructive pulmonary diseaseBiochemical and Biophysical Research Communications, 2005
- The role of tumour‐associated macrophages in tumour progression: implications for new anticancer therapiesThe Journal of Pathology, 2002
- Patterns and Emerging Mechanisms of the Angiogenic Switch during TumorigenesisCell, 1996
- Dormancy of micrometastases: Balanced proliferation and apoptosis in the presence of angiogenesis suppressionNature Medicine, 1995
- What Is the Evidence That Tumors Are Angiogenesis Dependent?JNCI Journal of the National Cancer Institute, 1990
- Tumor Angiogenesis: Therapeutic ImplicationsThe New England Journal of Medicine, 1971