Inhibition of Glycosphingolipid Biosynthesis Induces Cytokinesis Failure

Abstract

Although cells undergo dramatic shape changes during cytokinesis, the role of the plasma membrane and lipids is poorly understood. We report that inactivation of glucosyl ceramide synthase (GCS), either by RNAi or with the small molecule PPMP, causes failure of cleavage furrow ingression. Using mass spectrometry-based global lipid profiling, we identify individual lipids that are enhanced or depleted due to GCS inhibition. We show that GCS inhibition results in the mis-localization of actin and the ERM proteins, key cytoskeletal proteins that connect the plasma membrane to the actin cortex. Our data suggest that ceramides participate in mediating the interactions between the membrane and the cortex.

Animal cell cytokinesis: The role of dynamic changes in the plasma membrane proteome and lipidome

“…Eight of the 11 species identified as accumulating in cytokinesis were sphingolipids derivatives, in particular a number of dihydroceramides [49]. Expressed at very low levels in non-dividing cells, the selective increase in dihydroceramides is suggestive of a specific role of this class of molecules during division, and is consistent with data showing that inhibition of glycosylceramide synthase caused cytokinesis failure [53].…”

Evolving concepts in cancer therapy through targeting sphingolipid metabolism

“…Conversely, over-expression of GCS conferred resistance to both TNFα and doxorubicin-induced apoptosis through suppression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and subsequent reactive oxygen species generation [79] Drugs designed to inhibit GCS in the context of Gaucher disease type 1 (lysosomal storage disorder) have been developed and show good specificity and are well tolerated [80]. However, caution in using GCS inhibitors is warranted as it has been reported that PPMP (along with RNAi) can cause cytokinesis failure and multinucleation in human cervical adenocarcinoma cells HeLa, which can lead to chemoresistance [81, 82]. …”

Glucosylceramide Transferase Activity Is Critical for Encystation and Viable Cyst Production by an Intestinal Protozoan, Giardia lamblia

“…PPMP is a common inhibitor of GlcT1 enzyme that has been extensively used to evaluate GlcCer functions in various organisms (41). It has been reported that PPMP blocks replication and cytokinesis of giardial trophozoites and is thereby thought to inhibit the encystation and cyst production in culture (18,26).…”