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Ligand-activated PPARδ modulates the migration and invasion of melanoma cells by regulating Snail expression
Sun Ah Ham1, Taesik Yoo1, Jung Seok Hwang1
1Department of Animal Biotechnology, Konkuk University 120 Neungdong-ro, Gwangjin-Gu, Seoul 143-701, Republic of Korea.
Abstract:
Peroxisome proliferator-activated receptor (PPAR) δ is implicated in the carcinogenesis of several types of cancer. However, the therapeutic efficacy of PPARδ ligands against cancer progression is unclear. Here, we showed that PPARδ modulates the migration and invasion of melanoma cells by up-regulating Snail expression. Activation of PPARδ by GW501516, a specific ligand for PPARδ, significantly increased the migration and invasion of highly metastatic A375SM cells, but not that of low metastatic A375P cells. The migration- and invasion-promoting effects of PPARδ on A375SM cells was associated with increased Snail expression, which was accompanied by a decrease in E-cadherin expression. Furthermore, a significant concentration- and time-dependent increase in the levels of Snail mRNA and protein was observed in A375SM cells (but not A375P cells) treated with GW501516. The effects of GW501516 were almost completely abrogated by a small interfering RNA against PPARδ, suggesting that PPARδ mediates the effects of GW501516. Activation of PPARδ in SK-MEL-2 and SK-MEL-5 (but not SK-MEL-3) melanoma cell lines also led to significant increases in the expression of Snail mRNA and protein, which mirrored the invasive and migratory potential of these cell lines. These results suggest that PPARδ promotes the aggressive phenotype observed in highly metastatic melanoma cells by up-regulating Snail.
Insights
Peroxisome proliferator-activated receptor (PPAR) delta activates Snail expression, promoting melanoma cell migration and invasion. This finding suggests PPAR delta as a potential therapeutic target for aggressive melanoma.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Peroxisome proliferator-activated receptor (PPAR) delta is linked to various cancers.
- The role of PPAR delta ligands in cancer progression remains uncertain.
- Understanding PPAR delta's function in melanoma is crucial for targeted therapies.
Purpose of the Study:
- To investigate the role of PPAR delta in melanoma cell migration and invasion.
- To determine if PPAR delta activation influences Snail expression in melanoma.
- To evaluate the therapeutic potential of PPAR delta ligands in melanoma.
Main Methods:
- Treatment of melanoma cell lines (A375SM, A375P, SK-MEL-2, SK-MEL-5, SK-MEL-3) with GW501516, a PPAR delta ligand.
- Assessment of cell migration and invasion.
- Analysis of Snail and E-cadherin expression using mRNA and protein levels.
- Gene silencing of PPAR delta using small interfering RNA (siRNA).
Main Results:
- GW501516 significantly increased migration and invasion in highly metastatic A375SM cells, but not in low metastatic A375P cells.
- PPAR delta activation led to increased Snail expression and decreased E-cadherin expression in metastatic melanoma cells.
- GW501516's effects were dependent on PPAR delta, as confirmed by siRNA knockdown.
- Similar effects were observed in other metastatic melanoma cell lines (SK-MEL-2, SK-MEL-5).
Conclusions:
- PPAR delta activation promotes aggressive phenotypes in highly metastatic melanoma cells.
- Upregulation of Snail expression by PPAR delta is a key mechanism driving melanoma cell migration and invasion.
- Targeting PPAR delta may offer a novel therapeutic strategy for combating metastatic melanoma.
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