Role of Sphingolipids and Metabolizing Enzymes in Hematological Malignancies

Abstract

Sphingolipids such as ceramide, sphingosine-1-phosphate and sphingomyelin have been emerging as bioactive lipids since ceramide was reported to play a role in human leukemia HL-60 cell differentiation and death. Recently, it is well-known that ceramide acts as an inducer of cell death, that sphingomyelin works as a regulator for microdomain function of the cell membrane, and that sphingosine-1-phosphate plays a role in cell survival/proliferation. The lipids are metabolized by the specific enzymes, and each metabolite could be again returned to the original form by the reverse action of the different enzyme or after a long journey of many metabolizing/synthesizing pathways. In addition, the metabolites may serve as reciprocal bio-modulators like the rheostat between ceramide and sphingosine-1-phosphate. Therefore, the change of lipid amount in the cells, the subcellular localization and the downstream signal in a specific subcellular organelle should be clarified to understand the pathobiological significance of sphingolipids when extracellular stimulation induces a diverse of cell functions such as cell death, proliferation and migration. In this review, we focus on how sphingolipids and their metabolizing enzymes cooperatively exert their function in proliferation, migration, autophagy and death of hematopoetic cells, and discuss the way developing a novel therapeutic device through the regulation of sphingolipids for effectively inhibiting cell proliferation and inducing cell death in hematological malignancies such as leukemia, malignant lymphoma and multiple myeloma.

Sphingomyelin generated by sphingomyelin synthase 1 is involved in attachment and infection with Japanese encephalitis virus

“…In addition, we tested the relationship of viral infection with endogenous SMase. There are two types of SMase related to cellular SM hydrolysis, neutral SMase and acid SMase which regulate various cellular functions such as proliferation, apoptosis, autophagy, and virus infection3031. However, inhibitors of both neutral SMase (GW 4869) and acid SMase (desipramine) had no effect on JEV infection (data not shown).…”

Regulation of membrane KCNQ1/KCNE1 channel density by sphingomyelin synthase 1

“…SMS catalyzes the conversion of phosphatidylcholine and ceramide to sphingomyelin and DAG. Two isoforms of SMS (SMS1 and SMS2) have been identified; SMS2 is found in the cytoplasmic membrane, whereas SMS1 is primarily localized in the Golgi apparatus (18,38). Both isoforms are shown here to be expressed in HEK-293T cells, but the focus here is on SMS1.…”

“…We next investigated the cellular mechanism by which SMS1 regulates the expression of KCNQ1/KCNE1 channels. SMS1 is known to reside in the Golgi apparatus and catalyzes the conversion of phosphatidylcholine and ceramide to sphingomyelin and DAG (18,38). Because SMS1 changed KCNQ1/ KCNE1 current density only, without changing channel properties, it is likely that SMS1 affects the trafficking of channel proteins to the cytoplasmic membrane, rather than modifying the channel proteins themselves.…”

“…SMS1 is one of the two isoforms of the enzyme that catalyzes the conversion of phosphatidylcholine and ceramide to sphingomyelin and diacylglycerol (DAG) (reviewed in Refs. 18,38). We showed that SMS1 deficiency results in hearing impairment, which is attributable to a reduction in endocochlear potential caused by aberrant KCNQ1 protein expression in the marginal cells of the stria vascularis of the inner ear (21).…”

Ceramide as a Target of Marine Triterpene Glycosides for Treatment of Human Myeloid Leukemia

“…We describe these enzymes and their reactions. Their responsible genes, biochemical characteristics, subcellular localization and regulation were summarized by Kitatani et al [13]. …”