Intracellular Role for Sphingosine Kinase 1 in Intestinal Adenoma Cell Proliferation

Abstract

Sphingosine kinase (Sphk) enzymes are important in intracellular sphingolipid metabolism as well as in the biosynthesis of sphingosine 1-phosphate (S1P), an extracellular lipid mediator. Here, we show that Sphk1 is expressed and is required for small intestinal tumor cell proliferation in Apc Min/؉ mice. Adenoma size but not incidence was dramatically reduced in Apc Min/؉ Sphk ؊/؊ mice. Concomitantly, epithelial cell proliferation in the polyps was significantly attenuated, suggesting that Sphk1 regulates adenoma progression. Although the S1P receptors (S1P1R, S1P2R, and S1P3R) are expressed, polyp incidence or size was unaltered in Apc Min/؉ S1p2r ؊/؊ , Apc Min/؉ S1p3r ؊/؊ , and Apc Min/؉ S1p1r ؉/؊ bigenic mice. These data suggest that extracellular S1P signaling via its receptors is not involved in adenoma cell proliferation. Interestingly, tissue sphingosine content was elevated in the adenomas of Apc Min/؉ Sphk1 ؊/؊ mice, whereas S1P levels were not significantly altered. Concomitantly, epithelial cell proliferation and the expression of the G 1 /S cell cycle regulator CDK4 and c-myc were diminished in the polyps of Apc Min/؉ Sphk1 ؊/؊ mice. In rat intestinal epithelial (RIE) cells in vitro, Sphk1 overexpression enhanced cell cycle traverse at the G 1 /S boundary. In addition, RIE cells treated with sphingosine but not C6-ceramide exhibited reduced cell proliferation, reduced retinoblastoma protein phosphorylation, and cyclin-dependent kinase 4 (Cdk4) expression. Our findings suggest that Sphk1 plays a critical role in intestinal tumor cell proliferation and that inhibitors of Sphk1 may be useful in the control of intestinal cancer.The concept that sphingolipid metabolism is an important source of signaling lipids has gained considerable acceptance. For example, sphingomyelin, an abundant membrane phospholipid, is metabolized into lipid mediators such as sphingosine, ceramide, ceramide 1-phosphate, and sphingosine 1-phosphate (S1P) (9). S1P, synthesized by the action of sphingosine kinase (Sphk), is secreted by cells and functions as an extracellular mediator by activating a family of G-protein-coupled receptors termed S1PR1-5 (13, 19, 30). The generality of S1P signaling in vertebrates is underscored by recent findings that S1PRs are needed for a multitude of physiological processes, including heart and vascular development, angiogenesis, and immune cell trafficking (12). However, the physiological and pathological significance of intracellular sphingolipid metabolism in vertebrates is virtually unknown. However, a recent study showed that the inhibition of S1P lyase resulted in alterations in tissue S1P levels, which influenced T-cell trafficking and immune responses (35). The importance of sphingolipid metabolism is underscored by its impact on cell death, stress responses, metabolism, and animal development in unicellular (Saccharomyces cerevisiae and Dictyostelium discoidium) and multicellular (Caenorhabditis elegans and Drosophila melanogaster) eukaryotes (4,5,10,21,26,28).Mammals express two functiona...

Sphingosine-1-Phosphate Metabolism and Intestinal Tumorigenesis: Lipid Signaling Strikes Again

“…[79][80][81][82][83] A recent study demonstrated that Sphk1, the major enzyme necessary for synthesizing S1P, is required for enlargement of Min mouse adenomas, since Min mice that do not express this enzyme develop only small adenomas, in contrast to the significant number of large adenomas that developed in Min mice with intact Sphk1 expression. 84 Importantly, both S1P and sphingosine levels were high in Min mouse polyps compared to normal adjacent tissues, indicating that sphingolipid metabolism is abnormal in the neoplastic tissue. When we subsequently quantitated SPL expression in Min mouse adenomas and normal intestinal epithelium by immunohistochemistry and western blotting, we found SPL expression to be high in the intestinal villi, as expected.…”

Guanine nucleotides regulate sphingosine kinase 1 activation by eukaryotic elongation factor 1A and provide a mechanism for eEF1A-associated oncogenesis

“…SK1 has a crucial role in determining the cellular balance of pro-apoptotic ceramide and sphingosine and pro-proliferative, pro-survival S1P, and there is now substantial evidence that SK1 has a role in tumourigenesis (Cuvillier, 2008). For example, SK1 expression is elevated in a variety of human solid tumours (French et al, 2003), overexpression of SK1 in NIH 3T3 fibroblasts leads to their neoplastic transformation , chemical inhibition or genetic ablation of SK1 reduces tumour growth in vivo (French et al, 2003;Kohno et al, 2006;Kawamori et al, 2009) and SK inhibitors or a dominant-negative SK1 can reduce neoplastic cell transformation induced by oncogenic H-Ras .…”

A Metabolic Shift Favoring Sphingosine 1-Phosphate at the Expense of Ceramide Controls Glioblastoma Angiogenesis

“…SPHK1 overexpression results in oncogenic transformation of normal fibroblasts (15,16), whereas the absence of SPHK1 in mice protects against the development of colon adenomas (17,18). Up-regulation of SPHK1 has been observed in many different tumors, including breast (19,20), lung (21,22), colon (17,18), and glioma (23,24), and increased SPHK1 expression has been associated with a poor survival outcome in GBM (24) as well as breast (20) and lung cancer (22). This has made SPHK1 a target of interest in cancer for biotechnology and pharmaceutical companies.…”