Title | Intracellular role for sphingosine kinase 1 in intestinal adenoma cell proliferation. |
Publication Type | Journal Article |
Year of Publication | 2006 |
Authors | Kohno M, Momoi M, Oo MLin, Paik J-H, Lee Y-M, Venkataraman K, Ai Y, Ristimaki AP, Fyrst H, Sano H, Rosenberg D, Saba JD, Proia RL, Hla T |
Journal | Mol Cell Biol |
Volume | 26 |
Issue | 19 |
Pagination | 7211-23 |
Date Published | 2006 Oct |
ISSN | 0270-7306 |
Keywords | Adenomatous Polyps, Animals, Apoptosis, Cell Cycle Proteins, Cell Differentiation, Cell Proliferation, Down-Regulation, G1 Phase, Gastrointestinal Neoplasms, Gene Deletion, Gene Expression Regulation, Neoplastic, Humans, Intestinal Mucosa, Lysophospholipids, Mice, Neovascularization, Pathologic, Phosphotransferases (Alcohol Group Acceptor), Rats, Receptors, Lysosphingolipid, RNA, Messenger, S Phase, Sphingosine |
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. |
DOI | 10.1128/MCB.02341-05 |
Alternate Journal | Mol Cell Biol |
PubMed ID | 16980623 |
PubMed Central ID | PMC1592880 |
Grant List | CA77528 / CA / NCI NIH HHS / United States HL70694 / HL / NHLBI NIH HHS / United States P01 CA077839 / CA / NCI NIH HHS / United States P01 HL070694 / HL / NHLBI NIH HHS / United States R37 HL067330 / HL / NHLBI NIH HHS / United States R01 HL067330 / HL / NHLBI NIH HHS / United States R01 CA077528 / CA / NCI NIH HHS / United States CA77839 / CA / NCI NIH HHS / United States HL67330 / HL / NHLBI NIH HHS / United States |
Related Faculty:
Ji-Hye Paik, Ph.D.