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Review
. 2013;117:59-89.
doi: 10.1016/B978-0-12-394274-6.00003-0.

Ceramide Glycosylation Catalyzed by Glucosylceramide Synthase and Cancer Drug Resistance

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Free PMC article
Review

Ceramide Glycosylation Catalyzed by Glucosylceramide Synthase and Cancer Drug Resistance

Yong-Yu Liu et al. Adv Cancer Res. .
Free PMC article

Abstract

Glucosylceramide synthase (GCS), converting ceramide to glucosylceramide, catalyzes the first reaction of ceramide glycosylation in sphingolipid metabolism. This glycosylation by GCS is a critical step regulating the modulation of cellular activities by controlling ceramide and glycosphingolipids (GSLs). An increase of ceramide in response to stresses, such as chemotherapy, drives cells to proliferation arrest and apoptosis or autophagy; however, ceramide glycosylation promptly eliminates ceramide and consequently, these induced processes, thus protecting cancer cells. Further, persistently enhanced ceramide glycosylation can increase GSLs, participating in selecting cancer cells to drug resistance. GCS is overexpressed in diverse drug-resistant cancer cells and in tumors of breast, colon, and leukemia that display poor response to chemotherapy. As ceramide glycosylation by GCS is a rate-limiting step in GSL synthesis, inhibition of GCS sensitizes cancer cells to anticancer drugs and eradicates cancer stem cells. Mechanistic studies indicate that uncoupling ceramide glycosylation can modulate gene expression, decreasing MDR1 through the cSrc/β-catenin pathway and restoring p53 expression via RNA splicing. These studies not only expand our knowledge in understanding how ceramide glycosylation affects cancer cells but also provide novel therapeutic approaches for targeting refractory tumors.

Figures

Fig. 1
Fig. 1
Basic structures of ceramide, glucosylceramide, galactosylceramide and globotriosylceramide. In mammals, the prevalent ceramide is C18-ceramide, which has a sphinganine chain length of 18 carbon atoms, with an E double bond between C4 and C5 and a C18 fatty acid acylating its C-2 amino. Glucose or galactose is attached to the 1-hydroxy group of ceramide to form glucosylceramide or galactosylceramide. A series of glycosylations transfer galactose units to the glucose moiety of glucosylceramide to generate varies GSLs, such as globotriaosylceramide.
Fig. 2
Fig. 2
Glycosphingolipid biosynthesis and its cellular functions. SPT, serine-palmitoyl transferase; CerS, ceramide synthase; CERT, ceramide transporter; GCS, glucosylceramide synthase; GalCerS, galactosylceramide synthase; GALC, galactocerebrosidase (β-galactosidase); LacCerS, lactosylceramide synthase; Gb3S, globotriaosylceramide synthase; GCase, glucocerebrosidase (β-glucosidase); GLA, α-galactosidase A; GM2S, GM2 synthase; GM3S, GM3 synthase; GEMs, GSL-enriched microdomains.
Fig. 3
Fig. 3
Cells exposed to drugs upregulate drug-resistant genes via actions of ceramide and GSLs. Ceramide, generated by de novo synthesis in response to stresses, transactivates GCS expression, possibly by way of the MAPK or PKC cascades and the Sp1 transcription factor; globo-series GSLs (Gb3, Gb5) interact with lipids/protein on GEMs and activate the cSrc-GSK cascade, consequently increasing the recruitment of β-catenin/Tcf-4 to upregulate MDR1. MAPK, mitogen-activated protein kinase; GEMs, GSL-enriched microdomains; GSK, glycogen synthase kinase-3.
Fig. 4
Fig. 4
Targeting ceramide glycosylation by GCS.

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