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Ligand-activated PPARγ downregulates CXCR4 gene expression through a novel identified PPAR response element and
Daniela Rovito1,2, Giulia Gionfriddo1, Ines Barone1
1Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy.
Abstract:
Stromal Derived Factor-1α (SDF-1α) and its cognate receptor CXCR4 play a key role in mediating breast cancer cell invasion and metastasis. Therefore, drugs able to inhibit CXCR4 activation may add critical tools to reduce tumor progression, especially in the most aggressive form of the breast cancer disease. Peroxisome Proliferator-Activated Receptor (PPAR) γ, a member of the nuclear receptor superfamily, has been found to downregulate CXCR4 gene expression in different cancer cells, however the molecular mechanism underlying this effect is not fully understood. Here, we identified a novel PPARγ-mediated mechanism that negatively regulates CXCR4 expression in both epithelial and stromal breast cancer cells. We found that ligand-activated PPARγ downregulated CXCR4 transcriptional activity through the recruitment of the silencing mediator of retinoid and thyroid hormone receptor (SMRT) corepressor onto a newly identified PPAR response element (PPRE) within the CXCR4 promoter in breast cancer cell lines. As a consequence, the PPARγ agonist rosiglitazone (BRL) significantly inhibited cell migration and invasion and this effect was PPARγ-mediated, since it was reversed in the presence of the PPARγ antagonist GW9662. According to the ability of cancer-associated fibroblasts (CAFs), the most abundant component of breast cancer stroma, to secrete high levels of SDF-1α, BRL reduced migratory promoting activities induced by conditioned media (CM) derived from CAFs and affected CXCR4 downstream signaling pathways activated by CAF-CM. In addition, CAFs exposed to BRL showed a decreased expression of CXCR4, a reduced motility and invasion along with a phenotype characterized by an altered morphology. Collectively, our findings provide novel insights into the role of PPARγ in inhibiting breast cancer progression and further highlight the utility of PPARγ ligands for future therapies aimed at targeting both cancer and surrounding stromal cells in breast cancer patients.
Insights
Peroxisome Proliferator-Activated Receptor (PPAR) γ activation inhibits breast cancer metastasis by downregulating CXCR4 expression. This novel mechanism involves SMRT corepressor recruitment, reducing cancer cell and cancer-associated fibroblast invasion.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Stromal Derived Factor-1α (SDF-1α) and its receptor CXCR4 are crucial for breast cancer invasion and metastasis.
- Peroxisome Proliferator-Activated Receptor (PPAR) γ is known to downregulate CXCR4, but the mechanism is unclear.
Purpose of the Study:
- To elucidate the novel PPARγ-mediated mechanism for downregulating CXCR4 expression in breast cancer.
- To investigate the therapeutic potential of PPARγ ligands in inhibiting breast cancer progression.
Main Methods:
- Investigated PPARγ-mediated regulation of CXCR4 expression in breast cancer cell lines.
- Utilized PPARγ agonists (rosiglitazone) and antagonists (GW9662) to assess effects on cell migration and invasion.
- Analyzed the impact of PPARγ activation on cancer-associated fibroblasts (CAFs) and their interaction with cancer cells.
Main Results:
- Ligand-activated PPARγ recruits SMRT corepressor to a PPRE in the CXCR4 promoter, reducing its transcription.
- Rosiglitazone significantly inhibited breast cancer cell migration and invasion, effects dependent on PPARγ activity.
- PPARγ activation reduced SDF-1α-mediated pro-migratory signaling from CAFs and decreased CAF motility and invasion.
Conclusions:
- Identified a novel PPARγ-SMRT-CXCR4 pathway that suppresses breast cancer cell and stromal cell invasion.
- PPARγ ligands demonstrate therapeutic potential for targeting both cancer cells and the tumor microenvironment in breast cancer.
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