DHA-mediated enhancement of TRAIL-induced apoptosis in colon cancer cells is associated with engagement of mitochondria and specific alterations in sphingolipid metabolism
DHA-mediated enhancement of TRAIL-induced apoptosis in colon cancer cells is associated with engagement of mitochondria and specific alterations in sphingolipid metabolism
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DOI：
10.1016/j.bbalip.2014.06.005
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发表时间：
2014-09-01
影响因子：
4.8
通讯作者：
Vaculova, Alena Hyrslova
中科院分区：
文献类型：
--
作者：
Skender, Belma;Hofmanova, Jifina;Vaculova, Alena Hyrslova
二十二碳六烯酸（DHA）是一种存在于鱼油中的n-3多不饱和脂肪酸，当单独使用或与某些抗癌药物联合使用时，可能会对结肠癌细胞产生细胞毒性和/或细胞抑制作用。在这里，我们证明了亚毒性剂量的DHA的选择性能力，以提高抗增殖和凋亡作用的临床有用的细胞因子TRAIL（肿瘤坏死因子相关的凋亡诱导配体）在癌症，但不是正常的人结肠细胞。DHA介导的TRAIL诱导的细胞凋亡的刺激与线粒体途径的广泛参与有关（Bax/巴克激活、线粒体膜电位下降、细胞色素c释放）、内质网应激反应激活（CHOP上调，PERK水平变化），细胞凋亡抑制蛋白减少（XIAP，cIAP 1）水平和鞘脂代谢（神经酰胺，己糖基神经酰胺，鞘磷脂，鞘氨醇的细胞内水平; HPLC/MS/MS）的显著变化。有趣的是，我们发现用DHA和TRAIL处理的癌症和正常结肠细胞之间的各种类型的神经酰胺（特别是C16：0，C24：1）的代表性存在显著差异，并表明它们在调节细胞对药物组合的反应中的潜在作用。这些研究结果突出了DHA与TRAIL的新组合疗法的潜力，通过同时靶向凋亡途径中的多个步骤来选择性消除结肠癌细胞。(C)2014爱思唯尔有限公司版权所有。
Docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid present in fish oil, may exert cytotoxic and/or cytostatic effects on colon cancer cells when applied individually or in combination with some anticancer drugs. Here we demonstrate a selective ability of subtoxic doses of DHA to enhance antiproliferative and apoptotic effects of clinically useful cytokine TRAIL (tumor necrosis factor-related apoptosis inducing ligand) in cancer but not normal human colon cells. DHA-mediated stimulation of TRAIL-induced apoptosis was associated with extensive engagement of mitochondrial pathway (Bax/Bak activation, drop of mitochondrial membrane potential, cytochrome c release), activation of endoplasmic reticulum stress response (CHOP upregulation, changes in PERK level), decrease of cellular inhibitor of apoptosis protein (XIAP, cIAP1) levels and significant changes in sphingolipid metabolism (intracellular levels of ceramides, hexosyl ceramides, sphingomyelines, sphingosines; HPLC/MS/MS). Interestingly, we found significant differences in representation of various classes of ceramides (especially C16:0, C24:1) between the cancer and normal colon cells treated with DHA and TRAIL, and suggested their potential role in the regulation of the cell response to the drug combination. These study outcomes highlight the potential of DHA for a new combination therapy with TRAIL for selective elimination of colon cancer cells via simultaneous targeting of multiple steps in apoptotic pathways. (C) 2014 Elsevier B.V. All rights reserved.