title: Glucose availability and glycolytic metabolism dictate glycosphingolipid levels.
abstract: Cancer therapeutics has seen an emergence and re-emergence of two metabolic fields in recent years, those of bioactive sphingolipids and glycolytic metabolism. Anaerobic glycolysis and its implications in cancer have been at the forefront of cancer research for over 90 years. More recently, the role of sphingolipids in cancer cell metabolism has gained recognition, notably ceramide's essential role in programmed cell death and the role of the glucosylceramide synthase (GCS) in chemotherapeutic resistance. Despite this knowledge, a direct link between these two fields has yet to be definitively drawn. Herein, we show that in a model of highly glycolytic cells, generation of the glycosphingolipid (GSL) glucosylceramide (GlcCer) by GCS was elevated in response to increased glucose availability, while glucose deprivation diminished GSL levels. This effect was likely substrate dependent, independent of both GCS levels and activity. Conversely, leukemia cells with elevated GSLs showed a significant change in GCS activity, but no change in glucose uptake or GCS expression. In a leukemia cell line with elevated GlcCer, treatment with inhibitors of glycolysis or the pentose phosphate pathway (PPP) significantly decreased GlcCer levels. When combined with pre-clinical inhibitor ABT-263, this effect was augmented and production of pro-apoptotic sphingolipid ceramide increased. Taken together, we have shown that there exists a definitive link between glucose metabolism and GSL production, laying the groundwork for connecting two distinct yet essential metabolic fields in cancer research. Furthermore, we have proposed a novel combination therapeutic option targeting two metabolic vulnerabilities for the treatment of leukemia.
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky.
authors.forename: Morgan
authors.initials: M
authors.lastname: Stathem
authors.forename: Subathra
authors.initials: S
authors.lastname: Marimuthu
authors.forename: Julie
authors.initials: J
authors.lastname: O'Neal
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Rathmell
authors.forename: Jason A
authors.initials: JA
authors.lastname: Chesney
authors.forename: Levi J
authors.initials: LJ
authors.lastname: Beverly
authors.forename: Leah J
authors.initials: LJ
authors.lastname: Siskind
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D002518:Ceramides / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D005964:Glucosyltransferases / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006028:Glycosphingolipids / Q000378:metabolism*; D006801:Humans; D013107:Sphingolipids / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D000814:Aniline Compounds; D002518:Ceramides; D006028:Glycosphingolipids; D013107:Sphingolipids; D013449:Sulfonamides; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; D005947:Glucose; C528561:navitoclax
keywords: 2-DEOXYGLUCOSE; 2-DG; 6-AMINONICATINOMIDE; 6-AN; ABT-263; ABT-737; APOPTOSIS; CERAMIDE; GCS; GLUCOSE; GLUCOSYLCERAMIDE; GLUCOSYLCERAMIDE SYNTHASE; GLYCOLYSIS; GLYCOSPHINGOLIPID; GSL; GlcCer; GluCer; METABOLISM; PENTOSE PHOSPHATE PATHWAY; PPP; SPHINGOLIPID