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PNAS 105 (45): 17402-17407

Copyright © 2008 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / CELL BIOLOGY

Ceramide starves cells to death by downregulating nutrient transporter proteins

Garret G. Guenthera,1, Eigen R. Peraltaa,1, Kimberly Romero Rosalesa,1, Susan Y. Wonga, Leah J. Siskindb, and Aimee L. Edingera,2

aDepartment of Developmental and Cell Biology, University of California, Irvine, CA 92697; and bMedical University of South Carolina, Department of Medicine, Division of General Internal Medicine/Geriatrics, Charleston, SC 29425

Edited by Doug R. Green, St. Jude Hospital, Memphis, TN, and accepted by the Editorial Board September 26, 2008

Received for publication March 19, 2008.

Abstract: Ceramide induces cell death in response to many stimuli. Its mechanism of action, however, is not completely understood. Ceramide induces autophagy in mammalian cells maintained in rich media and nutrient permease downregulation in yeast. These observations suggested to us that ceramide might kill mammalian cells by limiting cellular access to extracellular nutrients. Consistent with this proposal, physiologically relevant concentrations of ceramide produced a profound and specific downregulation of nutrient transporter proteins in mammalian cells. Blocking ceramide-induced nutrient transporter loss or supplementation with the cell-permeable nutrient, methyl pyruvate, reversed ceramide-dependent toxicity. Conversely, cells became more sensitive to ceramide when nutrient stress was increased by acutely limiting extracellular nutrients, inhibiting autophagy, or deleting AMP-activated protein kinase (AMPK). Observations that ceramide can trigger either apoptosis or caspase-independent cell death may be explained by this model. We found that methyl pyruvate (MP) also protected cells from ceramide-induced, nonapoptotic death consistent with the idea that severe bioenergetic stress was responsible. Taken together, these studies suggest that the cellular metabolic state is an important arbiter of the cellular response to ceramide. In fact, increasing nutrient demand by incubating cells in high levels of growth factor sensitized cells to ceramide. On the other hand, gradually adapting cells to tolerate low levels of extracellular nutrients completely blocked ceramide-induced death. In sum, these results support a model where ceramide kills cells by inducing intracellular nutrient limitation subsequent to nutrient transporter downregulation.

Key Words: autophagy • caspase-independent cell death • daunorubicin • bioenergetics • sphingolipid


Author contributions: G.G.G., E.R.P., K.R.R., S.Y.W., L.J.S., and A.L.E. designed research; G.G.G., E.R.P., K.R.R., S.Y.W., L.J.S., and A.L.E. performed research; L.J.S. contributed new reagents/analytic tools; G.G.G., E.R.P., K.R.R., S.Y.W., L.J.S., and A.L.E. analyzed data; and A.L.E. wrote the paper.

1G.G.G., E.R.P., and K.R.R. contributed equally to this work.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission. D.R.G. is a guest editor invited by the Editorial Board.

This article contains supporting information online at www.pnas.org/cgi/content/full/0802781105/DCSupplemental.

2To whom correspondence should be addressed. E-mail: aedinger{at}uci.edu

© 2008 by The National Academy of Sciences of the USA


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