title: Oncogenic K-Ras regulates bioactive sphingolipids in a sphingosine kinase 1-dependent manner.
abstract: Sphingosine kinase 1 (SK1) is an important enzyme involved in the production of the bioactive lipid sphingosine 1-phosphate (S1P). SK1 is overexpressed in many forms of cancer, however, the contribution of SK1 to cancer progression is still unclear. One of the best characterized mutations found in several forms of human cancer is an activating point mutation in the Ras oncogene, which disrupts its GTPase activity and leads to stimulation of the MEK/ERK pathway. Because SK1 activity and subcellular localization have been shown to be regulated by ERK, we wished to investigate the effect of oncogenic Ras, a potent activator of the Raf/MEK/ERK pathway, on the activity of SK1 and sphingolipid metabolism. Using HEK293T cells transiently transfected with the K-RasG12V oncogene and both wild type and Sphk1(-/-) mouse embryonic fibroblasts stably infected with retroviral K-RasG12V, we found that K-RasG12V increases the production of S1P and decreases the production of ceramide in a SK1-dependent manner. In addition, we found that expression of the K-RasG12V oncogene leads to plasma membrane localization of SK1 and a reduction in cytosolic levels of SK1. This effect is likely mediated by the Raf/MEK/ERK pathway as constitutively active B-Raf or MEK1 are able to activate SK1, but constitutively active Akt1 is not. We believe this research has important implications for how sphingolipids may be contributing to oncogenic transformation and provide some of the first evidence for oncogenes inducing specific changes in sphingolipid metabolism through SK1 regulation.
authors: Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina 29401, USA.
authors: Christopher R
authors: CR
authors: Gault
authors: Scott T
authors: ST
authors: Eblen
authors: Carola A
authors: CA
authors: Neumann
authors: Yusuf A
authors: YA
authors: Hannun
authors: Lina M
authors: LM
authors: Obeid
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism* / Q000502:physiology; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism* / Q000502:physiology; D013107:Sphingolipids / Q000737:chemistry*; D013347:Subcellular Fractions / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism* / Q000502:physiology; D000099157:Sphingosine Kinase
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D013107:Sphingolipids; D018631:ras Proteins; D000099157:Sphingosine Kinase; C117307:KRAS protein, human; C495971:Hras protein, mouse