Sun Hongxia, Chung Wen-Cheng, Ryu Seung-Hee, Ju Zhenlin, Tran Hai T, Kim Edward, Kurie Jonathan M, Koo Ja Seok
Department of Thoracic/Head and Neck Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Cancer Prev Res (Phila). 2008 Oct;1(5):316-28. doi: 10.1158/1940-6207.CAPR-07-0002.
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.
血管生成在肿瘤进展中的重要性已得到认可，这促使抗血管生成成为癌症治疗和预防的新策略。据报道，促炎细胞因子白细胞介素（IL）-1β通过调节肿瘤微环境和诱导血管生成来促进肿瘤发展。然而，介导IL-1β诱导非小细胞肺癌（NSCLC）血管生成的因素以及IL-1β对这些血管生成因子的调节尚不清楚。在此，我们报告，通过微阵列分析确定，IL-1β上调了NSCLC细胞系A549和正常人气管支气管上皮细胞中一系列促血管生成的CXC趋化因子基因。进一步分析显示，IL-1β在NSCLC细胞中诱导的CXC趋化因子蛋白水平远高于正常人气管支气管上皮细胞。IL-1β处理的A549细胞的条件培养基显著增加了内皮细胞迁移，而针对CXCL5和CXCR2的中和抗体可抑制这种迁移。我们还发现，敲低环磷酸腺苷反应元件结合蛋白（CREB）或核因子κB（NF-κB）可消除IL-1β诱导的NSCLC细胞中CXC趋化因子基因的过表达。此外，与正常、癌前永生化或非致瘤细胞系相比，致瘤性NSCLC细胞系中CXC趋化因子基因的表达以及CREB和NF-κB活性大大增加。CREB结合蛋白与转录因子（如CREB和NF-κB）之间相互作用的破坏剂2-萘酚-AS-E-磷酸盐（KG-501）可抑制IL-1β诱导的NSCLC细胞中CXC趋化因子基因表达和血管生成活性。我们提出，使用小分子抑制剂（如KG-501）靶向CREB或NF-κB有望成为NSCLC的预防和/或治疗方法。
