Sphingosine kinase 1 in cancer.

The role of sphingolipids as bioactive signaling molecules that can regulate cell fate decisions puts them at center stage for cancer treatment and prevention. While ceramide and sphingosine have been established as antigrowth molecules, sphingosine-1-phosphate (S1P) offers a progrowth message to cells. The enzymes responsible for maintaining the balance between these "stop" or "go" signals are the sphingosine kinases (SK), SK1 and SK2. While the relative contribution of SK2 is still being elucidated and may involve an intranuclear role, a substantial amount of evidence suggests that regulation of sphingolipid levels by SK1 is an important component of carcinogenesis. Here, we review the literature regarding the role of SK1 as an oncogene that can function to enhance cancer cell viability and promote tumor growth and metastasis; highlighting the importance of developing specific SK1 inhibitors to supplement current cancer therapies.

Regulation of CC ligand 5/RANTES by acid sphingomyelinase and acid ceramidase.

Acid sphingomyelinase (aSMase) generates the bioactive lipid ceramide (Cer) from hydrolysis of sphingomyelin (SM). However, its precise roles in regulating specific sphingolipid-mediated biological processes remain ill defined. Interestingly, the aSMase gene gives rise to two distinct enzymes, lysosomal sphingomyelinase (L-SMase) and secretory sphingomyelinase (S-SMase) via alternative trafficking of a shared protein precursor. Previously, our laboratory identified Ser(508) as a crucial residue for the constitutive and regulated secretion of S-SMase in response to inflammatory cytokines, and demonstrated a role for S-SMase in formation of select cellular Cer species (Jenkins, R. W., Canals, D., Idkowiak-Baldys, J., Simbari, F., Roddy, P., Perry, D. M., Kitatani, K., Luberto, C., and Hannun, Y. A. (2010) J. Biol. Chem. 285, 35706-35718). In the present study using a chemokine/cytokine screen, we identified the chemokine CCL5 (formerly known as RANTES) as a candidate-specific downstream target for aSMase. Regulation of CCL5 by aSMase was subsequently validated using both loss-of-function and gain-of-function models indicating that aSMase is both necessary and sufficient for CCL5 production. Interestingly, cells deficient in acid ceramidase (aCDase) also exhibited defects in CCL5 induction, whereas cells deficient in sphingosine kinase-1 and -2 exhibited higher levels of CCL5, suggesting that sphingosine and not sphingosine 1-phosphate (S1P) is responsible for the positive signal to CCL5. Consistent with this, co-expression of aSMase and aCDase was sufficient to strongly induce CCL5. Taken together, these data identify a novel role for aSMase (particularly S-SMase) in chemokine elaboration by pro-inflammatory cytokines and highlight a novel and shared function for aSMase and aCDase.

p53 and regulation of bioactive sphingolipids.

Both the sphingolipid and p53 pathways are important regulators- and apparent collaborators-of cell-fate decisions. Whereas some investigations have suggested that ceramide and more complex sphingolipids function upstream of p53 or in a p53-independent manner, other studies propose that p53-dependent alterations in these sphingolipids can also contribute to apoptosis. Further studies focusing on sphingolipid metabolizing enzymes have revealed that they function similarly both upstream and downstream of p53 activation. However, whereas various components of the sphingolipid and p53 pathways may simultaneously function to elicit apoptosis and/or growth inhibition, SMase and SK1 may undergo explicit regulation by p53 that could contribute to ceramide-induced senescence in cells. Thus, we propose that regulation of bioactive sphingolipid signaling molecules could be of therapeutic benefit in the treatment of p53-dependent cancers.