A glycosylated antitumor ether lipid kills cells via paraptosis-like cell death
A glycosylated antitumor ether lipid kills cells via paraptosis-like cell death
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DOI：
10.1139/o08-147
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发表时间：
2009-04-01
影响因子：
2.9
通讯作者：
Arthur, Gilbert
中科院分区：
文献类型：
--
作者：
Samadder, Pranati;Bittman, Robert;Arthur, Gilbert
糖基化抗肿瘤醚脂（GAEL）相对于烷基溶血磷脂类具有上级抗癌特性，但尚未有关于这些化合物的机制的研究。原型盖尔，1-O-十六烷基-2-O-甲基-3-O-（2 '-氨基-2'-脱氧-β-D-吡喃葡萄糖基）-sn-甘油（Gln），有效地杀死缺乏参与半胱天冬酶依赖性凋亡的关键分子的小鼠胚胎成纤维细胞（MEF），并且半胱天冬酶抑制剂不能阻止细胞死亡。谷氨酰胺没有引起线粒体膜电位的损失，即使在圆形的垂死细胞。Gln刺激了多种细胞（包括野生型MEF）中自噬蛋白标记物LC 3-II的出现和积累，但在缺乏ATG 5（自噬所需的关键蛋白）的MEF中却没有。谷氨酰胺在稳定表达LC 3-绿色荧光蛋白融合蛋白的中国仓鼠卵巢细胞中诱导LC 3斑点形成。因此，谷氨酰胺似乎诱导自噬。自噬不依赖于mTOR，并且不被3-甲基腺嘌呤或渥曼青霉素抑制。尽管Gln具有毒性，但细胞进行自噬的能力并不是其毒性所必需的。此外，盖尔类似物2-脱氧-C-Glc诱导LC 3斑点形成，但不杀死细胞。谷氨酰胺，而不是2-脱氧-C-葡萄糖，引起细胞质中的酸性空泡的积累。我们的数据表明，GAELs可能会激活自噬，然而，GAELs不杀死细胞的凋亡或自噬，而是通过paraptosis-like细胞死亡机制。
Glycosylated antitumor ether lipids (GAELs) have superior anticancer properties relative to the alkyllysophospholipid class, but there have been no studies of the mechanisms of these compounds. The prototype GAEL, 1-O-hexadecyl-2-O-methyl-3-O-(2'-amino-2'-deoxy-beta-D-glucopyranosyl)-sn-glycerol (Gln), effectively killed mouse embryonic fibroblasts (MEFs) lacking key molecules involved in caspase-dependent apoptosis, and cell death was not prevented by caspase inhibitors. Gln did not cause a loss of mitochondrial membrane potential, even in rounded-up dying cells. Gln stimulated the appearance and accumulation of LC3-II, a protein marker for autophagy, in a variety of cells, including wild-type MEFs, but not in MEFs lacking ATG5, a key protein required for autophagy. Gln induced LC3 puncta formation in Chinese hamster ovary cells stably expressing a LC3-green fluorescent protein fusion protein. Thus, Gln appears to induce autophagy. Autophagy was mTOR-independent and was not inhibited by 3-methyladenine or wortmannin. Although Gln is toxic, cellular ability to undergo autophagy was not essential for its toxicity. Furthermore, the GAEL analog 2-deoxy-C-Glc induced LC3 puncta formation but did not kill the cells. Gln, but not 2-deoxy-C-Glc, caused the accumulation of cytoplasmic acidic vacuoles in the cells. Our data suggest that GAELs may activate autophagy; however, GAELs do not kill cells by apoptosis or autophagy but rather by a paraptosis-like cell death mechanism.