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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 Cells¹

Department of Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-82, Japan

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.

¹ This work was supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Education, Science, Sports and Culture, Japan.

² To whom requests for reprints should be addressed, at Department of Genetics, Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka 812-82, Japan. Phone: 81-92-642-6827; Fax: 81-92-632-0150.

Received 8/ 4/97. Accepted 9/17/97.

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