Sphinganine causes early activation of JNK and p38 MAPK and inhibition of AKT activation in HT-29 human colon cancer cells.
The sphingoid base sphinganine induces apoptosis in HT-29 human colon cancer cells more potently than other bioactive sphingolipid metabolites sphingosine and C2-ceramide tested in our previous study. The objective of this study was to investigate the effect of sphinganine, at a concentration that induces apoptosis, on the mitogen activated protein kinases (MAPKs) including ERK1/ERK2, JNK2/JNK1, and p38 MAPK and AKT (protein kinase B), which regulate cell proliferation and apoptosis. HT-29 cells were cultured with sphinganine at 35 microM and the protein expression and phosphorylation status of ERK1/ERK2 (p44/p42), JNK2/JNK1 (p54/p46), p38 MAPK, and AKT were determined using Western blot analysis. Sphinganine clearly increased the active phosphorylated forms of JNK2/JNK1 and p38 MAPK after 15, 30, and 60 min treatment, with minimal effects on activation of ERK1/ERK2. Sphinganine weakly inhibited the phosphorylation of AKT at ser473 after 30 and 60 min. Sphinganine had little or no effect on the protein expression level of any of the kinases. The findings are consistent with a mechanism by which sphinganine induces apoptosis in HT-29 cells via early and strong activation of JNK and p38 MAPK and weak inhibition of AKT activation.
Ahn
Eun Hyun
EH
Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI 48824-1224, USA. ahne@mail.med.upenn.edu
Schroeder
Joseph J
JJ
D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D048056:Mitogen-Activated Protein Kinase 9; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048055:Mitogen-Activated Protein Kinase 8; D048051:p38 Mitogen-Activated Protein Kinases; D013110:Sphingosine; C005682:safingol