Date on Master's Thesis/Doctoral Dissertation

8-2014

Document Type

Master's Thesis

Degree Name

M.S.

Department

Pharmacology and Toxicology

Committee Chair

Siskind, Leah J.

Committee Co-Chair (if applicable)

Beverly, Levi

Committee Member

Beverly, Levi

Committee Member

Clark, Geoff

Committee Member

Clem, Brian

Subject

Glycolysis; Sphingolipids; Cancer cells; Leukemia--Treatment

Abstract

Cancer therapeutics has seen an emergence and re-emergence of two metabolic fields in recent years, namely bioactive sphingolipids and glycolytic metabolism. Anaerobic glycolysis and its role in cancer has been recognized in cancer biology over 90 years. In recent decades, 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 concretely 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 significantly decreased GlcCer levels. When combined with pre-clinical inhibitor ABT-263, this effect was augmented and production of proapoptotic 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.

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