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Survival regulation in pancreatic cancer cells by c-Jun
Yoshiyuki Okutomi1, Yuji Shino, Fumitake Komoda
1Department of Medicine and Clinical Oncology (K1), Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
Abstract:
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.
Insights
Activating K-ras mutations are common in pancreatic cancer. However, the MEK kinase 1 (MEKK1)-c-Jun N-terminal kinase (JNK)-c-Jun pathway does not inhibit cancer cell survival, unlike in other cells.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Over 90% of human pancreatic cancers have K-ras gene mutations at codon 12.
- The role of K-ras downstream pathways in pancreatic cancer cell survival and proliferation is not fully understood.
- The MEK kinase 1 (MEKK1)-c-Jun N-terminal kinase (JNK)-c-Jun pathway is implicated in cell proliferation, survival, and apoptosis.
Purpose of the Study:
- To investigate the role of the JNK-c-Jun pathway, downstream of MEKK1, in the survival of human pancreatic cancer cells.
- To determine if c-Jun activation inhibits pancreatic cancer cell survival, as it does in non-pancreatic cancer cells.
Main Methods:
- Dominant-negative MEKK1 (DN-MEKK) was used to inhibit the MEKK1 pathway.
- Colony formation assays were performed to assess cell survival.
- Reporter gene assays (Gal4-c-Jun) and gel retardation assays were used to evaluate c-Jun activity.
Main Results:
- c-Jun failed to inhibit the survival of pancreatic cancer cell lines.
- In contrast, c-Jun significantly inhibited the survival of non-pancreatic cancer cells.
- c-Jun was found to be activated in growing pancreatic cancer cells, but this activation did not prevent cell survival.
Conclusions:
- The MEKK1-JNK-c-Jun pathway does not function as a negative regulator of cell survival in pancreatic cancer cells.
- c-Jun activation does not inhibit pancreatic cancer cell survival, differing from its effect in non-pancreatic cancer cells.
- Understanding these mechanisms may offer new therapeutic strategies for pancreatic cancer treatment.