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Troglitazone increases expression of E-cadherin and claudin 4 in human pancreatic cancer cells
Shima Kumei1, Wataru Motomura, Takayuki Yoshizaki
1Department of General Medicine, Asahikawa Medical College, midorigaoka-higashi 2-1-1, Asahikawa, Hokkaido 078-8510, Japan.
Abstract:
We examined the effects of troglitazone on expression of E-cadherin and claudin 4 in human pancreatic cancer cells. Troglitazone dose-dependently increased expression of E-cadherin and claudin 4 mRNA and protein in PK-1 cells. Snail, Slug and ZEB1, mRNAs were not changed by troglitazone, indicating that these three transcriptional repressors would not play a role in the induction of E-cadherin by troglitazone. GW9662, a PPARgamma antagonist, failed to block the increased expression of E-cadherin or claudin 4 mRNA, suggesting a PPARgamma-independent pathway. A MEK inhibitor, U0126, increased E-cadherin or claudin 4 mRNA and protein expression, and potently inhibited cell invasion. Because troglitazone down-regulates MEK-ERK signaling and inhibit cell invasion in PK-1 as shown in our previous study, these results suggest that troglitazone increases expression of E-cadherin and claudin 4 possibly through inhibition of MEK-ERK signaling in pancreatic cancer cells, which might be involved in the troglitazone-induced inhibition of cell invasive activity.
Insights
Troglitazone enhances E-cadherin and claudin 4 expression in pancreatic cancer cells, potentially by inhibiting MEK-ERK signaling. This mechanism may reduce cancer cell invasion.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Pancreatic cancer exhibits aggressive behavior and metastasis.
- E-cadherin and claudin 4 are crucial cell adhesion molecules.
- Understanding molecular regulators of pancreatic cancer invasion is vital.
Purpose of the Study:
- To investigate the effects of troglitazone on E-cadherin and claudin 4 expression in human pancreatic cancer cells.
- To elucidate the signaling pathways involved in troglitazone's action.
- To explore the potential of troglitazone in modulating pancreatic cancer cell invasiveness.
Main Methods:
- Human pancreatic cancer PK-1 cells were treated with varying concentrations of troglitazone.
- Quantitative real-time PCR and Western blotting were used to assess mRNA and protein expression levels.
- The roles of PPARgamma and MEK-ERK signaling pathways were investigated using specific inhibitors (GW9662 and U0126).
- Cell invasion assays were performed to evaluate the functional impact of troglitazone treatment.
Main Results:
- Troglitazone significantly increased E-cadherin and claudin 4 mRNA and protein expression in a dose-dependent manner.
- Troglitazone's effects were independent of PPARgamma signaling, as shown by the lack of blockade by GW9662.
- Inhibition of MEK-ERK signaling by U0126 mimicked troglitazone's effect on E-cadherin and claudin 4 expression and inhibited cell invasion.
- Snail, Slug, and ZEB1 mRNA levels remained unchanged, suggesting they are not involved in troglitazone-induced E-cadherin upregulation.
Conclusions:
- Troglitazone enhances E-cadherin and claudin 4 expression in pancreatic cancer cells.
- The mechanism appears to involve the inhibition of the MEK-ERK signaling pathway, independent of PPARgamma.
- These findings suggest a potential therapeutic role for troglitazone in reducing pancreatic cancer cell invasion.
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