Saltar al contenido
Merck

Glucose availability and glycolytic metabolism dictate glycosphingolipid levels.

Journal of cellular biochemistry (2014-08-26)
Morgan Stathem, Subathra Marimuthu, Julie O'Neal, Jeffrey C Rathmell, Jason A Chesney, Levi J Beverly, Leah J Siskind
RESUMEN

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.

MATERIALES
Referencia del producto
Marca
Descripción del producto

Sigma-Aldrich
Metanol, suitable for HPLC, ≥99.9%
Sigma-Aldrich
Metanol, ACS reagent, ≥99.8%
Sigma-Aldrich
Metanol, suitable for HPLC, gradient grade, ≥99.9%
Sigma-Aldrich
HEPES, ≥99.5% (titration)
Sigma-Aldrich
Metanol, HPLC Plus, ≥99.9%
Sigma-Aldrich
HEPES, BioPerformance Certified, ≥99.5% (titration), suitable for cell culture
Sigma-Aldrich
Metanol, anhydrous, 99.8%
Sigma-Aldrich
Metanol, suitable for HPLC, gradient grade, suitable as ACS-grade LC reagent, ≥99.9%
Sigma-Aldrich
Anti-β-actina monoclonal antibody produced in mouse, clone AC-15, ascites fluid
Sigma-Aldrich
Metanol, puriss. p.a., ACS reagent, reag. ISO, reag. Ph. Eur., ≥99.8% (GC)
Sigma-Aldrich
Metanol, Laboratory Reagent, ≥99.6%
Sigma-Aldrich
HEPES, BioUltra, for molecular biology, ≥99.5% (T)
Sigma-Aldrich
Anti-α-tubulina monoclonal antibody produced in mouse, ascites fluid, clone B-5-1-2
Sigma-Aldrich
HEPES buffer solution, 1 M in H2O
Sigma-Aldrich
Metanol, Absolute - Acetone free
Sigma-Aldrich
Metanol, BioReagent, ≥99.93%
Sigma-Aldrich
Metanol, ACS spectrophotometric grade, ≥99.9%
USP
Metanol, United States Pharmacopeia (USP) Reference Standard
SAFC
HEPES
Sigma-Aldrich
Metanol, ACS reagent, ≥99.8%