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.
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February 2009
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Conference Article|
January 20 2009
Starvation in the midst of plenty: making sense of ceramide-induced autophagy by analysing nutrient transporter expression
Aimee L. Edinger
Aimee L. Edinger
1
1Department of Developmental and Cell Biology, 2128 Natural Sciences 1, University of California Irvine, Irvine, CA 92697, U.S.A.
1email [email protected]
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Publisher: Portland Press Ltd
Received:
September 30 2008
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2009 Biochemical Society
2009
Biochem Soc Trans (2009) 37 (1): 253–258.
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Received:
September 30 2008
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Aimee L. Edinger; Starvation in the midst of plenty: making sense of ceramide-induced autophagy by analysing nutrient transporter expression. Biochem Soc Trans 1 February 2009; 37 (1): 253–258. doi: https://doi.org/10.1042/BST0370253
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