Ceramide-1-phosphate promotes cell survival through activation of the phosphatidylinositol 3-kinase/protein kinase B pathway

• Published in: FEBS letters 2005-07, Vol.579 (17), p.3744-3750
• Main Authors: Gómez-Muñoz, Antonio, Kong, Jennifer Y., Parhar, Kuljit, Wang, Shih Wei, Gangoiti, Patricia, González, Mónica, Eivemark, Sharlene, Salh, Bill, Duronio, Vincent, Steinbrecher, Urs P.
• Format: Article
• Language: English
• Subjects: 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt; A-SMase; acetyl; acid sphingomyelinase; Animals; Apoptosis; bcl-X Protein; BMDM; Bone Marrow Cells - metabolism; bone marrow-derived macrophages; C1P; caffeic acid phenylethyl ester; calcium-dependent cytosolic phospholipase A2; CAPE; Cell Survival; Ceramide-1-phosphate; Ceramides - pharmacology; Ceramides - physiology; cPLA2; DNA-Binding Proteins - metabolism; electromobility shift assay; EMSA; ERK; extracellular regulated kinase; FBS; Female; fetal bovine serum; GAPDH; glyceraldehyde-3-phosphate dehydrogenase; I-kappa B Proteins - metabolism; M-CSF; macrophage colony stimulating factor; Macrophages - metabolism; MAPK; MAPK/ERK kinase; MEK; Mice; mitogen-activated protein kinase; MTS; NF-kappa B - metabolism; NF-κB; octanoyl; pertussis toxin; phenazine methosulfate; phosphatidylinositol; phosphatidylinositol (3,4,5) trisphosphate; phosphatidylinositol 3-kinase; Phosphatidylinositol 3-Kinases - drug effects; Phosphatidylinositol 3-Kinases - metabolism; phospholipase D; Phosphorylation - drug effects; PI (3,4,5) P3; PI3-K; PI3-kinase; PKB; PLD; PMS; Protein kinase B; Protein-Serine-Threonine Kinases - drug effects; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - drug effects; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2 - metabolism; PTX; S1P; Sphingomyelinase; sphingosine-1-phosphate; TBS; thin-layer chromatography; TLC; Tris-buffered saline; Up-Regulation
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2005.05.067

In this report, we show for the first time that ceramide-1-phosphate (C1P) stimulates the phosphatidylinositol 3-kinase (PI3-K)/protein kinase B (PKB) pathway, which is a major mechanism whereby growth factors promote cell survival. Also, C1P induced IκB phosphorylation, and enhanced the DNA binding activity of the transcription factor NF-κB. Apoptotic macrophages showed a marked reduction of Bcl-X L levels, and this was prevented by C1P. These findings suggest that C1P blocks apoptosis, at least in part, by stimulating the PI3-K/PKB/ NF-κB pathway and maintaining the production of antiapoptotic Bcl-X L. Based on these and our previous observations, we propose a working model for C1P in which inhibition of acid sphingomyelinase and the subsequent decrease in ceramide levels would allow cell signaling through stimulation of the PI3-K/PKB pathway to promote cell survival.