Activated Ki-ras enhances sensitivity of ceramide-induced apoptosis without c-Jun NH2-terminal kinase/stress-activated protein kinase or extracellular signal-regulated kinase activation in human colon cancer cells.
The activation of c-Jun NH2-terminal kinase (JNK)/stress-activated protein kinase (SAPK) and/or extracellular signal-regulated kinase (ERK) is involved in ceramide-induced apoptosis in certain cells. To examine the relationship between activated Ki-ras-mediated signals and ceramide-induced apoptosis in human colon cancer cells, JNK/SAPK and ERK activity, as initiated by ceramide, was examined in HCT116, which has a mutation of Ki-ras at codon 13, and HCT116-derived clones, HKe-3 and HKh-2, in which activated Ki-ras was disrupted through gene targeting. In HKe-3 and HKh-2, the activity of JNK/SAPK increased significantly within 60 min following C2 ceramide stimulation, and some apoptosis followed. In contrast, C2 ceramide caused a marked apoptosis in HCT116, but activation of JNK/SAPK was not observed. C2 ceramide did not activate ERK in any of the cell lines. These results suggest that activated Ki-ras contributes to the sensitivity of ceramide-induced apoptosis without JNK/SAPK or ERK activation and that other signaling pathways involved in ceramide-induced apoptosis may be present in human colon cancer cells.
Ohmori
M
M
Department of Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Shirasawa
S
S
Furuse
M
M
Okumura
K
K
Sasazuki
T
T
D017209:Apoptosis / Q000235:genetics; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D002518:Ceramides / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000473:pathology; D053938:DNA Fragmentation; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D011905:Genes, ras / Q000502:physiology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D002518:Ceramides; D019908:Proto-Oncogene Proteins c-raf; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases