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Ablation of sphingosine kinase-2 inhibits tumor cell proliferation and migration.
- Source :
-
Molecular cancer research : MCR [Mol Cancer Res] 2011 Nov; Vol. 9 (11), pp. 1509-19. Date of Electronic Publication: 2011 Sep 06. - Publication Year :
- 2011
-
Abstract
- Sphingosine kinases (SK) regulate the balance between proapoptotic ceramides and mitogenic sphingosine-1-phosphate (S1P); however, the functions of the two isoenzymes (SK1 and SK2) in tumor cells are not well defined. Therefore, RNA interference was used to assess the individual roles of SK1 and SK2 in tumor cell sphingolipid metabolism, proliferation, and migration/invasion. Treatment of A498, Caki-1, or MDA-MB-231 cells with siRNAs specific for SK1 or SK2 effectively suppressed the expression of the target mRNA and protein. Ablation of SK1 did not affect mRNA or protein levels of SK2 and reduced intracellular levels of S1P while elevating ceramide levels. In contrast, ablation of SK2 elevated mRNA, protein, and activity levels of SK1 and increased cellular S1P levels. Interestingly, cell proliferation and migration/invasion were suppressed more by SK2-selective ablation than by SK1-selective ablation, showing that the increased S1P does not rescue these phenotypes. Similarly, exogenous S1P did not rescue the cells from the antiproliferative or antimigratory effects of the siRNAs. Consistent with these results, differential effects of SK1- and SK2-selective siRNAs on signaling proteins, including p53, p21, ERK1, ERK2, FAK, and VCAM1, indicate that SK1 and SK2 have only partially overlapping functions in tumor cells. Overall, these data indicate that loss of SK2 has stronger anticancer effects than does suppression of SK1. Consequently, selective inhibitors of SK2 may provide optimal targeting of this pathway in cancer chemotherapy.<br /> (Mol Cancer Res; 9(11); 1509-19. ©2011 AACR.)
- Subjects :
- Cell Growth Processes physiology
Cell Line, Tumor
Cell Movement physiology
Gene Knockdown Techniques
Humans
Isoenzymes
Phosphotransferases (Alcohol Group Acceptor) biosynthesis
Phosphotransferases (Alcohol Group Acceptor) genetics
RNA, Small Interfering administration & dosage
RNA, Small Interfering genetics
Signal Transduction
Transfection
Neoplasms enzymology
Neoplasms pathology
Phosphotransferases (Alcohol Group Acceptor) deficiency
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3125
- Volume :
- 9
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Molecular cancer research : MCR
- Publication Type :
- Academic Journal
- Accession number :
- 21896638
- Full Text :
- https://doi.org/10.1158/1541-7786.MCR-11-0336