Fenretinide induces lethal autophagy via a novel ensemble of life and death regulators: dihydroceramide and sphinganine versus sphinganine 1-phosphate

Abstract

Sphingolipids are unique lipids that serve numerous functions important in cell regulation. Some categories of sphingolipids have also been implicated in the mechanism of action of cancer chemotherapeutic drugs, with the hypothesis being that these drugs are effective because they alter sphingolipid metabolic pathways to increase the production of ceramide, a sphingolipid known to induce cell death. Fenretinide (4-hydroxyphenylretinamide, 4HPR) is one such drug and has been thought to induce apoptosis through an increase of ceramide biosynthesis. However, recent research by W. Zheng et.al 2006., has shown that fenretinide instead increases dihydroceramide, which has traditionally been regarded as innocuous in cell signaling. This study has explored how fenretinide induces cell death via elevation of dihydroceramide and has discovered that dihydroceramide and fenretinide are both potent inducers of autophagy, a pathway for turnover of cell constituents that can also trigger type II programmed cell death. In addition, this analysis has found that after dihydroceramide induces the formation of autophagosomes, it seems to be further metabolized to sphinganine and sphinganine 1-phosphate as indicated by an increase in the quantity of these species and whether or not this results in cell death depends on the balance between these highly bioactive toxic (sphinganine) versus anti-apoptotic (sphinganine-1-phosphate) compounds. Thus, these studies suggest that the mechanism of fenretinide toxicity has many components: elevation of dihydroceramide to induce autophagy as well as changes in sphinganine and sphinganine-1-phosphate, with the balance between the latter dictating if the autophagy is lethal.