Survival regulation in pancreatic cancer cells by c-Jun.
Over 90% of human pancreatic cancers harbor an activating point mutation in the K-ras gene at codon 12. However, it is not clear whether all downstream K-ras are activated and which downstream contributes to the cell survival and proliferation of pancreatic cancer cells. MEK kinase 1 (MEKK1)-c-Jun N-terminal kinase (JNK)-c-Jun pathway has an important role in cell proliferation, survival and apoptosis in various cells. We previously demonstrated that the dominant negative form of MEKK1 (DN-MEKK) inhibits the survival of human pancreatic cancer cell lines. In this study we investigated whether JNK-c-Jun, the downstream pathway of DN-MEKK, affects the survival of human pancreatic cancer cell lines. Colony formation assays indicated that c-Jun failed to inhibit the survival of pancreatic cancer cells, whereas c-Jun remarkably inhibited the cell survival of non-pancreatic cancer cells. Reporter gene assays using Gal4-c-Jun and gel retardation assays indicated that c-Jun functions were activated in growing pancreatic cancer cells. These results revealed that c-Jun activation does not prevent the cell survival of pancreatic cancer cells in contrast to non-pancreatic cancer cells. It appears that MEKK1-JNK-c-Jun pathway fails to act as a negative regulator for the cell survival of pancreatic cancer cells. Greater understanding of these mechanisms may be helpful in the treatment of pancreatic cancer.
Okutomi
Yoshiyuki
Y
Department of Medicine and Clinical Oncology (K1), Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
Shino
Yuji
Y
Komoda
Fumitake
F
Hirano
Tatsuya
T
Ishihara
Takeshi
T
Yamaguchi
Taketo
T
Saisho
Hiromitsu
H
Shirasawa
Hiroshi
H
D017209:Apoptosis; D015153:Blotting, Western; D002453:Cell Cycle; D002455:Cell Division; D045744:Cell Line, Tumor; D002470:Cell Survival; D004247:DNA / Q000737:chemistry; D016193:G1 Phase; D005799:Genes, Dominant; D017930:Genes, Reporter; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation; D010179:Pancreas / Q000166:cytology; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D010957:Plasmids / Q000378:metabolism; D017354:Point Mutation; D015533:Transcriptional Activation
D004247:DNA; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases