Starvation in the midst of plenty: making sense of ceramide-induced autophagy by analysing nutrient transporter expression
Starvation in the midst of plenty: making sense of ceramide-induced autophagy by analysing nutrient transporter expression
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DOI：
10.1042/bst0370253
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发表时间：
2009-02-01
影响因子：
3.9
通讯作者：
Edinger, Aimee L.
中科院分区：
文献类型：
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作者：
Edinger, Aimee L.
神经酰胺诱导哺乳动物细胞分化、增殖停滞、衰老和死亡。神经酰胺产生这些结果的机制已被证明难以定义。基于神经酰胺刺激自噬的观察结果，我们已经确定了这种鞘脂的一种新的作用机制：神经酰胺在营养转运蛋白下调后使细胞饿死。在酵母中，响应于热应激而产生的神经酰胺通过下调营养渗透酶而适应性地减缓细胞生长。在哺乳动物细胞中，致命剂量的神经酰胺通过严重限制细胞对细胞外营养物的获取而引发生物能量危机，使得自噬不足以满足细胞的代谢需求。与神经酰胺毒性的生物能量学解释一致，丙酮酸甲酯（一种膜渗透性营养物）保护细胞免受神经酰胺诱导的饥饿。同样与该模型一致的是，我们发现细胞的代谢状态决定了其对神经酰胺的敏感性。因此，癌细胞对神经酰胺的敏感性增加可能与其不灵活的生物合成代谢程序有关。这些研究强调了评估自噬细胞中营养转运蛋白表达的价值，以及培养条件在确定细胞对神经酰胺的反应中所起的重要作用。
Ceramide induces differentiation, proliferative arrest, senescence and death in mammalian cells. The mechanism by which ceramide produces these outcomes has proved difficult to define. Building on observations that ceramide stimulates autophagy, we have identified a novel mechanism of action for this sphingolipid: ceramide starves cells to death subsequent to profound nutrient transporter down-regulation. in yeast, ceramide generated in response to heat stress adaptively slows cell growth by down-regulating nutrient permeases. in mammalian cells, a lethal dose of ceramide triggers a bioenergetic crisis by so severely limiting cellular access to extracellular nutrients that autophagy is insufficient to meet the metabolic demands of the cell. in keeping with this bioenergetic explanation for ceramide toxicity, methyl pyruvate, a membrane-permeable nutrient, protects cells from ceramide-induced starvation. Also consistent with this model, we have found that the metabolic state of the cell determines its sensitivity to ceramide. Thus the increased sensitivity of cancer cells to ceramide may relate to their inflexible biosynthetic metabolic programme. These studies highlight the value of assessing nutrient transporter expression in autophagic cells and the important role that culture conditions play in determining the cellular response to ceramide.