PDF(Pubmed)
Abstract：
5-Lipoxygenase (5-LO), a fatty acid oxygenase, is the central enzyme in leukotriene (LT) biosynthesis, potent arachidonic acid-derived lipid mediators released by innate immune cells, that control inflammatory and allergic responses. In addition, through interaction with 12- and 15-lipoxgenases, the enzyme is involved in the formation of omega-3 fatty acid-based oxylipins, which are thought to be involved in the resolution of inflammation. The expression of 5-LO is frequently deregulated in solid and liquid tumors, and there is strong evidence that the enzyme plays an important role in carcinogenesis. However, global inhibition of LT formation and signaling has not yet shown the desired success in clinical trials. Curiously, the release of 5-LO-derived lipid mediators from tumor cells is often low, and the exact mechanism by which 5-LO influences tumor cell function is poorly understood. Recent data now show that in addition to releasing oxylipins, 5-LO can also influence gene expression in a lipid mediator-independent manner. These non-canonical functions, including modulation of miRNA processing and transcription factor shuttling, most likely influence cancer cell function and the tumor microenvironment and might explain the low clinical efficacy of pharmacological strategies that previously only targeted oxylipin formation and signaling by 5-LO. This review summarizes the canonical and non-canonical functions of 5-LO with a particular focus on tumorigenesis, highlights unresolved issues, and suggests future research directions.
摘要：
5-脂氧合酶(5-LO),脂肪酸加氧酶,是白三烯（LT）生物合成的中心酶，先天性免疫细胞释放的有效花生四烯酸衍生的脂质介质，控制炎症和过敏反应。此外,通过与12-和15-脂氧酶的相互作用，该酶参与基于omega-3脂肪酸的氧化脂素的形成，被认为与炎症的解决有关。5-LO的表达在实体和液体肿瘤中经常失调，有强有力的证据表明这种酶在致癌作用中起着重要作用。然而,LT形成和信号传导的整体抑制在临床试验中尚未显示出预期的成功。奇怪的是,从肿瘤细胞中释放5-LO衍生的脂质介质通常很低，5-LO影响肿瘤细胞功能的确切机制知之甚少。最近的数据显示，除了释放氧化脂外，5-LO还可以以不依赖脂质介质的方式影响基因表达。这些非规范函数，包括调节miRNA加工和转录因子穿梭，最有可能影响癌细胞功能和肿瘤微环境,并可能解释以前仅通过5-LO靶向羟脂素形成和信号传导的药理学策略的低临床疗效。这篇综述总结了5-LO的规范和非规范功能，特别关注肿瘤发生。突出未解决的问题，并提出了未来的研究方向。
