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.