A new take on ceramide: starving cells by cutting off the nutrient supply.

Ceramide generation is increased by a broad array of signals. In general, ceramide limits cell survival and proliferation and promotes differentiation and senescence. Despite its role in the pathogenesis of multiple human diseases, ceramide's mechanism of action remains poorly defined. Understanding how this sphingolipid modulates cell physiology is therefore an important goal. Building on prior observations that ceramide induces autophagy, we demonstrate that ceramide kills cells by inducing severe bioenergetic stress secondary to nutrient transporter downregulation. In support of this model, maintaining nutrient access blocks ceramide-induced autophagy and cell death. This bioenergetic mechanism of action may explain the increased sensitivity of cancer cells to ceramide. Starvation induces quiescence in normal cells. Tumor cells, in contrast, carry oncogenic mutations that block the switch to catabolism and prevent a reduction in metabolic demand leading to a bioenergetic crisis when nutrients become scarce. We propose that the non-lethal effects of ceramide might also stem from ceramide-induced starvation. While severe nutrient stress kills cells, mild nutrient limitation slows proliferation and may contribute to the induction of senescence. In sum, our new model for ceramide action suggests that regulated nutrient transporter expression may play a previously unappreciated role in cancer and other diseases where ceramide metabolism is altered.