Role for sphingosine kinase 1 in colon carcinogenesis.
Sphingosine kinase 1 (SphK1) phosphorylates sphingosine to form sphingosine-1-phosphate (S1P) and is a critical regulator of sphingolipid-mediated functions. Cell-based studies suggest a tumor-promoting function for the SphK1/S1P pathway. Also, our previous studies implicated the SphK1/S1P pathway in the induction of the arachidonic acid cascade, a major inflammatory pathway involved in colon carcinogenesis. Therefore, we investigated whether the SphK1/S1P pathway is necessary for mediating carcinogenesis in vivo. Here, we report that 89% (42/47) of human colon cancer samples stained positively for SphK1, whereas normal colon mucosa had negative or weak staining. Adenomas had higher expression of SphK1 vs. normal mucosa, and colon cancers with metastasis had higher expression of SphK1 than those without metastasis. In the azoxymethane (AOM) murine model of colon cancer, SphK1 and S1P were significantly elevated in colon cancer tissues compared to normal mucosa. Moreover, blood levels of S1P were higher in mice with colon cancers than in those without cancers. Notably, SphK1(-/-) mice subjected to AOM had significantly less aberrant crypt foci (ACF) formation and significantly reduced colon cancer development. These results are the first in vivo evidence that the SphK1/S1P pathway contributes to colon carcinogenesis and that inhibition of this pathway is a potential target for chemoprevention.
Kawamori
Toshihiko
T
Department of Pathology & Laboratory Medicine, Medical University of South Carolina, 165 Ashley Ave., Ste. 309, Charleston, SC 29425, USA. kawamori@musc.edu
Kaneshiro
Tatsuya
T
Okumura
Masae
M
Maalouf
Samer
S
Uflacker
Andre
A
Bielawski
Jacek
J
Hannun
Yusuf A
YA
Obeid
Lina M
LM
D000818:Animals; D001397:Azoxymethane / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016264:Dextran Sulfate / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008246:Lysophospholipids / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000096:biosynthesis; D000099157:Sphingosine Kinase
D001397:Azoxymethane; D051546:Cyclooxygenase 2; D016264:Dextran Sulfate; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate