Ablation of dihydroceramide desaturase confers resistance to etoposide-induced apoptosis in vitro.
Ablation of dihydroceramide desaturase confers resistance to etoposide-induced apoptosis in vitro.
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DOI：
10.1371/journal.pone.0044042
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Summers SA
中科院分区：
文献类型：
--
作者：
Siddique MM;Bikman BT;Wang L;Ying L;Reinhardt E;Shui G;Wenk MR;Summers SA
鞘脂生物合成被与细胞应激相关的因子有效地上调，包括许多化疗剂、炎性细胞因子和糖皮质激素。二氢神经酰胺去饱和酶1（Des 1）是驱动鞘脂生物合成的高度保守途径中的第三种酶，它引入了代表大多数高级鞘脂的4，5-反式双键。令人惊讶的是，最近的研究表明，某些化疗药物和其他药物抑制Des 1，产生了许多缺乏特征双键的鞘脂。为了评估改变鞘脂谱（通过Des 1抑制）对细胞功能的影响，我们产生了缺乏Des 1等位基因的同基因小鼠胚胎成纤维细胞。脂质组学分析显示，这些细胞含有比野生型成纤维细胞更高水平的二氢神经酰胺，并且复合鞘脂主要由饱和骨架组成（例如，鞘氨醇与鞘氨醇、二氢鞘磷脂与鞘磷脂等）。Des 1消融激活促存活和合成代谢信号传导中间体（例如Akt/PKB、mTOR、MAPK等）。并提供了对由依托泊苷引起的细胞凋亡的保护，依托泊苷是一种通过上调几种鞘脂生物合成酶来诱导鞘脂合成的化学治疗剂。这些数据表明，大多数鞘脂中存在的双键对细胞存活途径具有深远的影响，并且Des 1的操纵可能对细胞凋亡具有重要影响。
Sphingolipid biosynthesis is potently upregulated by factors associated with cellular stress, including numerous chemotherapeutics, inflammatory cytokines, and glucocorticoids. Dihydroceramide desaturase 1 (Des1), the third enzyme in the highly conserved pathway driving sphingolipid biosynthesis, introduces the 4,5-trans-double bond that typifies most higher-order sphingolipids. Surprisingly, recent studies have shown that certain chemotherapeutics and other drugs inhibit Des1, giving rise to a number of sphingolipids that lack the characteristic double bond. In order to assess the effect of an altered sphingolipid profile (via Des1 inhibition) on cell function, we generated isogenic mouse embryonic fibroblasts lacking both Des1 alleles. Lipidomic profiling revealed that these cells contained higher levels of dihydroceramide than wild-type fibroblasts and that complex sphingolipids were comprised predominantly of the saturated backbone (e.g. sphinganine vs. sphingosine, dihydrosphingomyelin vs. sphingomyelin, etc.). Des1 ablation activated pro-survival and anabolic signaling intermediates (e.g. Akt/PKB, mTOR, MAPK, etc.) and provided protection from apoptosis caused by etoposide, a chemotherapeutic that induces sphingolipid synthesis by upregulating several sphingolipid biosynthesizing enzymes. These data reveal that the double bond present in most sphingolipids has a profound impact on cell survival pathways, and that the manipulation of Des1 could have important effects on apoptosis.
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