Department of Clinical Innovative Medicine, Institute for Advancement of Clinical and Translational Science, Faculty of Medicine, Kyoto University, Kyoto, Japan.
Department of Clinical Innovative Medicine, Institute for Advancement of Clinical and Translational Science, Faculty of Medicine, Kyoto University, Kyoto, Japan.
Biochem Biophys Res Commun. 2014 Apr 4;446(2):460-4. doi: 10.1016/j.bbrc.2014.02.134. Epub 2014 Mar 12.
Aspirin has been widely used as analgesic, antipyretic and anti-inflammatory medicine for long. In addition to these traditional effects, clinical studies suggest that aspirin can protect against cancer, but its mechanism has not been explored. To unveil it, we identified the proteins up- or down-regulated after incubation with aspirin by using proteomics analysis with Nano-flow LC/MALDI-TOF system. Interestingly, the analysis identified the protein of Adenomatous Polyposis Coli (APC) as one of the most up-regulated protein. APC regulates cell proliferation or angiogenesis, and is widely known as a tumor-suppressing gene which can cause colorectal cancer when it is mutated. Western blots confirmed this result, and real-time PCR indicated it is transcriptionally regulated. We further tried to elucidate the molecular mechanism with focusing on IKKβ. IKKβ is the essential kinase in activation of nuclear factor-kappa B (NF-κB), major transcriptional factors that regulate genes responsible for inflammation or immune response. Previous reports indicated that aspirin specifically inhibits IKKβ activity, and constitutively active form of IKKβ accelerates APC loss. We found that aspirin suppressed the expression of IKKβ, and the deletion of IKKβ by siRNA increases the expression of APC in HEK294 cells. Finally, we observed similar effects of aspirin in human umbilical vein endothelial cells. Taken together, these results reveal that aspirin up-regulates the expression of APC via the suppression of IKKβ. This can be a mechanism how aspirin prevents cancer at least in part, and a novel link between inflammatory NF-κB signaling and cancer.
阿司匹林作为一种广泛使用的解热、镇痛和抗炎药物已经有很长时间了。除了这些传统作用外，临床研究表明阿司匹林可以预防癌症，但它的作用机制尚未被探索。为了揭示这一机制，我们使用纳流 LC/MALDI-TOF 系统进行蛋白质组学分析，鉴定出与阿司匹林孵育后上调或下调的蛋白质。有趣的是，分析发现腺瘤性结肠息肉病蛋白（APC）是上调最明显的蛋白质之一。APC 调节细胞增殖或血管生成，广泛认为是一种肿瘤抑制基因，当发生突变时会导致结直肠癌。Western blot 验证了这一结果，实时 PCR 表明其转录受到调控。我们进一步研究了 IKKβ 作为研究对象的分子机制。IKKβ 是核因子-kappa B（NF-κB）激活所必需的激酶，NF-κB 是调节炎症或免疫反应相关基因的主要转录因子。先前的报告表明，阿司匹林特异性抑制 IKKβ 的活性，而 IKKβ 的组成性激活形式加速 APC 的丢失。我们发现阿司匹林抑制了 IKKβ 的表达，而 siRNA 敲除 IKKβ 会增加 HEK294 细胞中 APC 的表达。最后，我们在人脐静脉内皮细胞中观察到阿司匹林的类似作用。总之，这些结果表明，阿司匹林通过抑制 IKKβ 而上调 APC 的表达。这可能是阿司匹林预防癌症的部分机制，也是炎症 NF-κB 信号和癌症之间的新联系。
