Chemoprevention via modulation of autophagy by sphingolipids

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DESCRIPTION (provided by applicant): Autophagy is a promising new target for cancer chemoprevention and chemotherapy because it has the potential to prevent, reverse, or retard progression of precancerous lesions as well as to kill tumor cells by "type II" or "autophagic" cell death. Inducers of autophagy that have been associated with cancer prevention and treatment include natural products such as resveratrol and synthetic compounds such as the anti- cancer drug fenretinide (4-hydroxy-phenylretinamide); nonetheless, the link between autophagy and cancer is complex because it also affords a means of survival for cancer cells during times of nutrient limitation and metabolic stress. Hence, the optimal agent, or combination of agents, would favor "lethal" versus "protective" autophagy. This grant application concerns a recently discovered mechanism for induction of autophagy that appears to control the switch between these outcomes. The mechanism involves the induction of autophagy by ceramides (Cer), dihydroceramides (DHCer), and sphingosine 1-phosphate (S1P), with the latter being a critical determinant of whether autophagy is lethal or protective. The underlying hypothesis of this research is that in the induction of autophagy, (DH)Cer are incorporated into autophagosomes and subsequently hydrolyzed (in autophagolysosomes) to sphinganine and sphingosine, which are cytotoxic unless phosphorylated by sphingosine kinase. Thus, the most effective scenario for chemoprevention and chemotherapy via autophagic cell death would be to favor the production of (DH)Cer and sphingoid bases over sphingoid base 1-phosphates. This intervention strategy will be explored using MCF7 cells that express GFP-tagged LC3 to facilitate the monitoring of autophagy, methods for "sphingolipidomic" analysis of changes in these lipid mediators, and tools that can manipulate sphingolipid metabolism as the cells are treated with two prototypic dietary and chemotherapeutic agents (resveratrol and 4HPR, respectively) as well as other compounds selected for mechanistic information they will provide. The findings of the studies could define a new concept in cancer chemoprevention and chemotherapy, and identify useful tools and biomarkers for evaluation of these and additional agents in laboratory and clinical follow- up studies.