Selenium suppresses leukemia through the action of endogenous eicosanoids.
Selenium suppresses leukemia through the action of endogenous eicosanoids.
复制标题
DOI：
10.1158/0008-5472.can-13-3694
复制
发表时间：
2014-07-15
期刊：
影响因子：
11.2
通讯作者：
Prabhu KS
中科院分区：
文献类型：
--
作者：
Gandhi UH;Kaushal N;Hegde S;Finch ER;Kudva AK;Kennett MJ;Jordan CT;Paulson RF;Prabhu KS
根除癌症干细胞(CSC)可能是彻底根除癌症的关键。CSC的代谢变化可能是其靶向的关键。在此，我们报告了膳食微量营养素硒在给予超生理但无毒剂量时可以触发慢性或急性髓系白血病来源的CSC的凋亡。在白血病CSC中，硒处理激活了ATM-P53依赖的细胞凋亡，并伴有细胞内活性氧水平的增加。重要的是，同样的治疗不会引发造血干细胞的凋亡。对表达bcr-abl基因的CSC进行的系列移植研究表明，小鼠体内的硒状态是CSC存活的关键决定因素。硒的作用依赖于环氧合酶衍生的前列腺素Δ12-PGJ2和15d-PGJ2的内源产生。因此，非类固醇抗炎药和NADPH氧化酶抑制剂取消了硒诱导白血病CSC凋亡的能力。我们的结果揭示了对花生四烯酸代谢的硒依赖调节如何能够直接触发原代人和小鼠白血病CSC的凋亡。
Eradicating cancer stem-like cells (CSC) may be essential to fully eradicate cancer. Metabolic changes in CSC could hold a key to their targeting. Here we report that the dietary micronutrient selenium can trigger apoptosis of CSC derived from chronic or acute myelogenous leukemias when administered at supraphysiological but non-toxic doses. In leukemia CSC, selenium treatment activated ATM-p53-dependent apoptosis accompanied by increased intracellular levels of reactive oxygen species. Importantly, the same treatment did not trigger apoptosis in hematopoietic stem cells. Serial transplantation studies with BCR-ABL-expressing CSC revealed that the selenium status in mice was a key determinant of CSC survival. Selenium action relied upon the endogenous production of the cyclooxygenase-derived prostaglandins Δ12-PGJ2 and 15d-PGJ2. Accordingly, non-steroidal anti-inflammatory drugs and NADPH oxidase inhibitors abrogated the ability of selenium to trigger apoptosis in leukemia CSC. Our results reveal how selenium-dependent modulation of arachidonic acid metabolism can be directed to trigger apoptosis of primary human and murine CSC in leukemia.