Editors' ChoiceCell death

Starving in the Midst of Plenty

Science Signaling  18 Nov 2008:
Vol. 1, Issue 46, pp. ec394
DOI: 10.1126/scisignal.146ec394

The sphingolipid ceramide elicits cell death in response to various stimuli, including withdrawal of growth factors, death receptor ligation, and exposure to chemotherapeutic drugs. Noting that ceramide triggers autophagy—a response to nutrient deprivation in which cells cannibalize their own cytoplasm—in mammalian cells exposed to abundant nutrients, Guenther et al. investigated the mechanisms underlying ceramide-induced autophagy and the relationship between ceramide-mediated autophagy and cell death. Analyses of the time course of ceramide-induced autophagy and cell death, combined with experiments in which progression of either autophagy or apoptosis was blocked, indicated that ceramide-induced autophagy was in fact a homeostatic response. Ceramide elicited a rapid decrease in the cell surface abundance of various proteins associated with amino acid or glucose transport at the cell surface, an effect that persisted when apoptosis was blocked and was found in various mammalian cell types. Nystatin, which disrupts lipid rafts, was protective against ceramide-mediated loss of nutrient transporters from the cell surface and ceramide-induced cell death. Moreover, a membrane-permeant form of pyruvate protected against ceramide-mediated cell death. Ceramide toxicity was influenced by cell metabolic state: Prolymphocytic FL5.12 cells grown in the presence of high concentrations of interleukin-3 (to elicit a highly glycolytic state) were more sensitive to ceramide-mediated cell death than were cells grown in the presence of low concentrations of interleukin-3. Similarly, cells adapted to growth in the presence of low concentrations of glucose and amino acids were resistant to ceramide-mediated cell death. The authors thus propose that ceramide decreases the abundance of cell surface nutrient transporters and thereby starves cells to death.

G. G. Guenther, E. R. Peralta, K. R. Rosales, S. Y. Wong, L. J. Siskind, A. L. Edinger, Ceramide starves cells to death by downregulating nutrient transporter proteins. Proc. Natl. Acad. Sci. U.S.A. 105, 17402–17407 (2008). [Abstract] [Full Text]