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 G1/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 G1/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.