title: Cyclic AMP-responsive element binding protein- and nuclear factor-kappaB-regulated CXC chemokine gene expression in lung carcinogenesis.
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)-1beta has been reported to promote tumor development. However, the factors mediating IL-1beta-induced angiogenesis in non-small cell lung cancer (NSCLC) and the regulation of these angiogenic factors by IL-1beta are less clear. Here, we report that IL-1beta 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-1beta induced much higher protein levels of CXC chemokines in NSCLC cells than in normal human tracheobronchial epithelium cells. Conditioned medium from IL-1beta-treated A549 cells markedly increased endothelial cell migration, which was suppressed by neutralizing antibodies against CXCL5 and CXCR2. We also found that IL-1beta-induced CXC chemokine gene overexpression in NSCLC cells was abrogated with the knockdown of cyclic AMP-responsive element binding protein (CREB) or nuclear factor kappaB (NF-kappaB). Moreover, the expression of the CXC chemokine genes as well as CREB and NF-kappaB 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-kappaB, 2-naphthol-AS-E-phosphate (KG-501), inhibited IL-1beta-induced CXC chemokine gene expression and angiogenic activity in NSCLC. We propose that targeting CREB or NF-kappaB using small-molecule inhibitors, such as KG-501, holds promise as a preventive and/or therapeutic approach for NSCLC.
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Sun
authors.forename: Wen-Cheng
authors.initials: WC
authors.lastname: Chung
authors.forename: Seung-Hee
authors.initials: SH
authors.lastname: Ryu
authors.forename: Zhenlin
authors.initials: Z
authors.lastname: Ju
authors.forename: Hai T
authors.initials: HT
authors.lastname: Tran
authors.forename: Edward
authors.initials: E
authors.lastname: Kim
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Kurie
authors.forename: Ja Seok
authors.initials: JS
authors.lastname: Koo
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000098:blood supply / Q000235:genetics* / Q000473:pathology; D002478:Cells, Cultured; D054365:Chemokine CXCL5 / Q000378:metabolism; D019743:Chemokines, CXC / Q000235:genetics* / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D016209:Interleukin-8 / Q000378:metabolism; D008175:Lung Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009284:Naphthols / Q000494:pharmacology; D009389:Neovascularization, Pathologic / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010755:Organophosphates / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology
chemical_list: C486263:CXCL5 protein, human; C508606:CXCL8 protein, human; D054365:Chemokine CXCL5; D019743:Chemokines, CXC; D017362:Cyclic AMP Response Element-Binding Protein; D053583:Interleukin-1beta; D016209:Interleukin-8; D016328:NF-kappa B; D009284:Naphthols; D010755:Organophosphates; D034741:RNA, Small Interfering; C495860:naphthol AS-E phosphate