Abstract B102: Fenretinide induces lethal autophagy via a novel ensemble of life and death regulators: dihydroceramide and sphinganine versus sphinganine 1-phosphate

Abstract

Abstract B102 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 4HPR is to increase the biosynthesis of ceramide, an inducer of apoptosis. Using liquid chromatography, electrospray ionization tandem mass spectrometry (LC ESI MS/MS) for “sphingolipidomic” analysis, we have found (H Wang et al., Mol. Cancer Ther. 7: 2967-2976, 2008) that 4HPR elevates dihydroceramides instead of ceramides due to the inhibition of dihydroceramide desaturase, and also increases the amounts of sphinganine and sphinganine 1-phosphate. In exploring how these metabolites could mediate 4HPR cytotoxicity, we have additionally 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 4HPR_and presumably other inhibitors of dihydroceramide desaturase--might be increased by concomitant inhibition of sphingosine kinase. (Acknowledgement: Some of these studies were conducted in collaboration with Dr. Myles Cabot of the John Wayne Cancer Institute, and funded by the Lipid MAPS Consortium grant GM069338.) Citation Information: Cancer Prev Res 2008;1(7 Suppl):B102.