title: 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 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.
authors.affiliation: Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, Farmington, CT 06030, USA.
authors.forename: Masataka
authors.initials: M
authors.lastname: Kohno
authors.forename: Michiko
authors.initials: M
authors.lastname: Momoi
authors.forename: Myat Lin
authors.initials: ML
authors.lastname: Oo
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Paik
authors.forename: Yong-Moon
authors.initials: YM
authors.lastname: Lee
authors.forename: Krishnan
authors.initials: K
authors.lastname: Venkataraman
authors.forename: Youxi
authors.initials: Y
authors.lastname: Ai
authors.forename: Ari P
authors.initials: AP
authors.lastname: Ristimaki
authors.forename: Henrik
authors.initials: H
authors.lastname: Fyrst
authors.forename: Hajime
authors.initials: H
authors.lastname: Sano
authors.forename: Daniel
authors.initials: D
authors.lastname: Rosenberg
authors.forename: Julie D
authors.initials: JD
authors.lastname: Saba
authors.forename: Richard L
authors.initials: RL
authors.lastname: Proia
authors.forename: Timothy
authors.initials: T
authors.lastname: Hla
mesh_terms: D018256:Adenomatous Polyps / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D015536:Down-Regulation / Q000235:genetics; D016193:G1 Phase / Q000502:physiology; D005770:Gastrointestinal Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000473:pathology; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D049349:Receptors, Lysosphingolipid / Q000235:genetics; D016196:S Phase / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D018797:Cell Cycle Proteins; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D012333:RNA, Messenger; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate