Sphingolipid Metabolism and Apoptosis
Ceramide (Cer) (N-acylsphingosine), sphingosine (Sph) and sphingosine-1-P (S-1P/S1P) are biosynthetically related bioactive sphingolipids that act as “second messengers” in the regulation of apoptosis. Ceramide and sphingosine promote apoptosis, whereas sphingosine-1-phosphate is anti-apoptotic. The balance, sphingolipid rheostat, between these pro- and anti-apoptotic sphingolipids determines the survival fate of various cells.
Sphingosine-1-phosphate is formed by type 1 and type 2 sphingosine kinases (SPHK1, SPHK2) that are activated by various growth and survival factors. SPHK1 is activated by ligand-occupied platelet derived growth factor receptors. Factors that promote the synthesis of S-1P typically deplete the ceramide and sphingosine pools and enhance cell survival. S-1P inhibits acidic sphingomyleinase (A-SMase). Ceramide accumulates in the cell by two principle mechanisms. It is synthesized from sphingomyelin (SM) by membrane-associated neutral sphingomyelinase (N-SMase) and/or endosomal acidic sphingomyelinase (A-SMase) and/or it is produced de novo by the activities of serine palmitoyltransferase (SPT) and ceramide synthase (CS). The SM pathway to generate ceramide is activated by tumor necrosis factor alpha (TNFa) and Fas receptors and by ionizing radiation. SMases are activated by binding to TNF receptor family death domains, FADD or TRADD. De novo synthesis of ceramide is stimulated by a variety of cytotoxic agents including etoposide, SDZ PSC 833, daunorubicin, phorbol ester and CPT-11. Ceramide may be further metabolized to free fatty acids and sphingosine, the precursor of S-1P, by neutral or acidic ceramidase.
Ceramide induced apoptosis is mediated via the mitochondria when ceramide is accumulated in the mitochondrial membrane. Ceramide activates protein phosphatase 2A (PP2A) which can dephosphorylate and inactivate the anti-apoptotic molecule, Bcl-2. Ceramide activation of PP2A competes with factors that phosphorylate and activate Bcl-2, such as PKCalpha. Ceramide enhances the translocation of the pro-apoptotic factor, Bax, to the mitochondria. Elevations of ceramide and sphingosine result in increased mitochondrial membrane permeabilization, cytochrome c release and activation of caspase 9 and effector caspases leading to cell death.
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