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

Abstract

Fenretinide (4-hydroxyphenylretinamide, 4HPR) is a promising anticancer agent that is being evaluated in human clinical trials. One of the proposed mechanisms of action for fenretinide is to increase the biosynthesis of ceramide, an inducer of apoptosis. Using LC ESI MS/MS for “sphingolipidomic” analysis of MCF7 cells, we find that fenretinide elevates dihydroceramides instead of ceramides (due to inhibition of dihydroceramide desaturase) and increases the amounts of sphinganine and sphinganine 1-phosphate. In exploring how these metabolites could mediate fenretinide cytotoxicity, we have discovered that dihydroceramides induce autophagy, and whether this is cytotoxic depends on the relative amounts of sphinganine 1-phosphate versus sphinganine--a highly toxic compound due to its effects on multiple signaling pathways as well as being lysosomotrophic. These findings reveal new facets of sphingolipid biology and autophagy, and suggest that the efficacy of fenretinide might be increased by concomitant inhibition of sphingosine kinase. (Acknowledgement: Studies were conducted in collaboration with Dr. Myles Cabot of the John Wayne Cancer Institute, and funded by the Lipid MAPS Consortium grant GM069338.)