Sphingolipid signaling and hematopoietic malignancies: to the rheostat and beyond

Abstract

Sphingosine-1-phosphate (S1P) is a bioactive lipid with diverse functions including the promotion of cell survival, proliferation and migration, as well as the regulation of angiogenesis, inflammation, immunity, vascular permeability and nuclear mechanisms that control gene transcription. S1P is derived from metabolism of ceramide, which itself has diverse and generally growth-inhibitory effects through its impact on downstream targets involved in regulation of apoptosis, senescence and cell cycle progression. Regulation of ceramide, S1P and the biochemical steps that modulate the balance and interconversion of these two lipids are major determinants of cell fate, a concept referred to as the "sphingolipid rheostat." There is abundant evidence that the sphingolipid rheostat plays a role in the origination, progression and drug resistance patterns of hematopoietic malignancies. The pathway has also been exploited to circumvent the problem of chemotherapy resistance in leukemia and lymphoma. Given the broad effects of sphingolipids, targeting multiple steps in the metabolic pathway may provide possible therapeutic avenues. However, new observations have revealed that sphingolipid signaling effects are more complex than previously recognized, requiring a revision of the sphingolipid rheostat model. Here, we summarize recent insights regarding the sphingolipid metabolic pathway and its role in hematopoietic malignancies.

Figure 1. Sphingolipid rheostat

S1P is produced from the conversion of sphingosine to S1P via SK enzymes. S1P is then shuttled to the extracellular space, where it can activate five known GPCRs. Upon activation, downstream signaling events occur to produce myriad effects. Ceramide can be produced via sphingomyelinases (SMase) by conversion of sphingomyelin to ceramide. Radiation, ROS, ischemia and TNFα can also contribute to ceramide generation. The traditional ‘rheostat’ model suggests a balance of forces between S1P and ceramide, with S1P promoting survival and ceramide promoting apoptosis. Downstream mediators affected by the rheostat include Bad, Bax, Bcl-XL and Mcl-1. Ceramide is also shown here to affect signaling via JNK and p38. Ceramide can also affect caspase activation and survivin suppression. Contrary to the ‘rheostat’ model, ceramide 16 promotes growth and inhibits the ER stress response in some cancers. SphK2 is also shown here to repress HDAC1/2 with subsequent upregulation of p21 and c-fos transcription.

Figure 2. S1P signaling in hematopoeitic malignancies

A.) The role of S1P in leukemia. i.) Sphingosine is converted by SphK1 into S1P and is exported to the extracellular space, where it can then activate S1P receptors. ii.) Upregulation of SphK1 inhibits cytochrome c transport to the cytoplasm. iii.) S1P activates S1P₁, which persistently activates the STAT3 pathway. iv.) STAT3 is transiently activated by IL-6 and travels to the nucleus for transcription. v.) Ceramide represses human telomerase (hTERT) promoter activity through HDAC-1-mediated deacetylation of sp3. B.) S1P signaling and apoptosis in lymphomas. i.) S1P₂ exerts a negative effect on B-cell lymphoma development, as S1P₂ knockout mice exhibit enhanced lymphoma formation. ii.) R(+)-methanandamide treatment results in decreased cell viability through increased ceramide synthase activity in mantle cell lymphoma. iii.) When SK is inhibited by DMS or SphK1 is inhibited by siRNA (*) in the presence of R(+)-methanandamide, cytochrome c induced apoptosis is potentiated in mantle cell lymphoma. C.) S1P signaling and apoptosis in Multiple Myeloma. i.) Mcl-2 anti-apoptotic effect is activated by S1P through S1P₁, S1P₂, and S1P₃. ii.) IL-6 confers an anti-apoptotic effect through activation of SphK1. iii.) IL-6 activation of SphK1 mediates conversion of sphingosine into S1P to prevent apoptosis.