COX inhibitors directly alter gene expression: role in cancer prevention?
COX inhibitors directly alter gene expression: role in cancer prevention?
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DOI：
10.1007/s10555-011-9301-4
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发表时间：
2011-12
期刊：
影响因子：
--
通讯作者：
Eling T
中科院分区：
文献类型：
--
作者：
Wang X;Baek SJ;Eling T
炎症是人类癌症发生和发展的重要因素。炎症性脂质代谢产物，前列腺素，由花生四烯酸通过前列腺素H合成酶（通常称为环氧化酶（cox））形成，与特定受体结合，激活驱动肿瘤发生和发展的信号通路。前列腺素形成抑制剂、COX抑制剂或非甾体抗炎药（NSAIDs）作为抑制肿瘤生长和长期使用可预防肿瘤发展的药物已被充分证明。非甾体抗炎药也改变基因表达而不依赖于COX抑制，这些基因表达的变化似乎也有助于这些药物的抗肿瘤活性。许多非甾体抗炎药，如sulindac sulfide，通过改变转录因子特异性蛋白1和早期生长反应-1的表达或磷酸化状态来改变基因表达，这两个事件之间的平衡导致特定靶基因的增加或减少。在这篇综述中，我们总结和讨论了非甾体抗炎药治疗后这种机制所改变的各种基因，以及这些表达变化与抗肿瘤活性的关系。综述的主要焦点是nsaid激活基因（NAG-1）或生长分化因子15。这个TGF-β超家族的独特成员被非甾体抗炎药和许多具有抗肿瘤活性的药物和化学物质高度诱导。对表达人类NAG-1的转基因小鼠的研究表明，它可以抑制几种癌症小鼠模型的肿瘤发展。讨论了NAG-1作为COX抑制剂预防癌症的潜在贡献者的生物化学和生物学。
Inflammation is an important contributor to the development and progression of human cancers. Inflammatory lipid metabolites, prostaglandins, formed from arachidonic acid by prostaglandin H synthases commonly called cyclooxygenases (COXs) bind to specific receptors that activate signaling pathways driving the development and progression of tumors. Inhibitors of prostaglandin formation, COX inhibitors, or nonsteroidal anti-inflammatory drugs (NSAIDs) are well documented as agents that inhibit tumor growth and with long-term use prevent tumor development. NSAIDs also alter gene expression independent of COX inhibition and these changes in gene expression also appear to contribute to the anti-tumorigenic activity of these drugs. Many NSAIDs, as illustrated by sulindac sulfide, alter gene expressions by altering the expression or phosphorylation status of the transcription factors specificity protein 1 and early growth response-1 with the balance between these two events resulting in increases or decreases in specific target genes. In this review, we have summarized and discussed the various genes altered by this mechanism after NSAID treatment and how these changes in expression relate to the anti-tumorigenic activity. A major focus of the review is on NSAID-activated gene (NAG-1) or growth differentiation factor 15. This unique member of the TGF-β superfamily is highly induced by NSAIDs and numerous drugs and chemicals with anti-tumorigenic activities. Investigations with a transgenic mouse expressing the human NAG-1 suggest it acts to suppress tumor development in several mouse models of cancer. The biochemistry and biology of NAG-1 were discussed as potential contributor to cancer prevention by COX inhibitors.