An oncogenic role for sphingosine kinase 2

Abstract

While both human sphingosine kinases (SK1 and SK2) catalyze the generation of the pleiotropic signaling lipid sphingosine 1-phosphate, these enzymes appear to be functionally distinct. SK1 has well described roles in promoting cell survival, proliferation and neoplastic transformation. The roles of SK2, and its contribution to cancer, however, are much less clear. Some studies have suggested an anti-proliferative/pro-apoptotic function for SK2, while others indicate it has a pro-survival role and its inhibition can have anti-cancer effects. Our analysis of gene expression data revealed that SK2 is upregulated in many human cancers, but only to a small extent (up to 2.5-fold over normal tissue). Based on these findings, we examined the effect of different levels of cellular SK2 and showed that high-level overexpression reduced cell proliferation and survival, and increased cellular ceramide levels. In contrast, however, low-level SK2 overexpression promoted cell survival and proliferation, and induced neoplastic transformation in vivo. These findings coincided with decreased nuclear localization and increased plasma membrane localization of SK2, as well as increases in extracellular S1P formation. Hence, we have shown for the first time that SK2 can have a direct role in promoting oncogenesis, supporting the use of SK2-specific inhibitors as anti-cancer agents.

Cell membrane modulation as adjuvant in cancer therapy

“…In this situation there are less Type 2 raft domains (Cer enriched) and less apoptosis. Sphingosine kinases regulate a number of process which aid tumor progression such as survival, proliferation and transformation which therefore provide possible targets for therapy [72]. …”

Validation of commercially available sphingosine kinase 2 antibodies for use in immunoblotting, immunoprecipitation and immunofluorescence

“…Of the many enzymes responsible for the biosynthesis and metabolism of sphingolipids, the sphingosine kinases (SKs) are of particular interest to study as they catalyze the formation of sphingosine 1-phosphate (S1P), and in doing so can promote cell survival, proliferation, migration and angiogenesis 2 . Both sphingosine kinases, SK1 and SK2, have been shown to be upregulated in various human cancers and both have documented roles in mediating oncogenesis 3, 4 . However, where SK1 and its roles in cancer development are relatively well characterized, SK2 remains somewhat enigmatic as, in addition to the pro-cancer functions it shares with SK1, SK2 can also facilitate cell cycle arrest and cell death 5, 6 .…”

Renal Mesangial Cells Isolated from Sphingosine Kinase 2 Transgenic Mice Show Reduced Proliferation and are More Sensitive to Stress-Induced Apoptosis

“…Additionally, high-SK-2 cells express the enzyme mainly in the nucleus whereas low-SK-2 cells express the enzyme mainly in the cytosol and at the plasma membrane. The authors also showed that a modest (2.5-fold) upregulation of SK-2 occurs in a broad range of cancers which led them to suggest that indeed, inhibition of SK-2 may have an anti-cancer potential [35].…”

“…In an attempt to explain the controversial results of SK-2 on proliferation and apoptosis of cancer cells, Neubauer et al proposed that the amount of SK-2 expression determines the cellular outcome [35]. This was based on studies performed in an inducible overexpression system where high-level overexpression of SK-2 in HEK293 cells (> 200-fold) reduced cell proliferation and survival, whereas low-level overexpression of SK-2 (in the range of 2-8-fold) promoted cell survival and proliferation [35].…”

“…This was based on studies performed in an inducible overexpression system where high-level overexpression of SK-2 in HEK293 cells (> 200-fold) reduced cell proliferation and survival, whereas low-level overexpression of SK-2 (in the range of 2-8-fold) promoted cell survival and proliferation [35]. Differences between the low-and high-SK-2 cells were found in the levels of ceramide subspecies and the subcellular localization of SK-2.…”