15-Deoxy-Δ^12,14-prostaglandin J₂ down-regulates CXCR4 on carcinoma cells through PPARγ- and NFκB-mediated pathways

The chemokine receptor CXCR4 plays a key role in the metastasis of colorectal cancer and its growth at metastatic sites. Here, we have investigated the mechanisms by which CXCR4 on cancer cells might be regulated by eicosanoids present within the colorectal tumor microenvironment. We show that prostaglandins PGE₂, PGA₂, PGD₂, PGJ₂ and 15dPGJ₂ each down-regulates CXCR4 receptor expression on human colorectal carcinoma cells to differing degrees. The most potent of these were PGD₂ and its metabolites PGJ₂ and 15dPGJ₂. Down-regulation was most rapid with the end-product 15dPGJ₂ and was accompanied by a marked reduction in CXCR4 mRNA. 15dPGJ₂ is known to be a ligand for the nuclear receptor PPARγ. Down-regulation of CXCR4 was also observed with the PPARγ agonist rosiglitazone, while 15dPGJ₂-induced CXCR4 down-regulation was substantially diminished by the PPARγ antagonists GW9662 and T0070907. These data support the involvement of PPARγ. However, the 15dPGJ₂ analogue CAY10410, which can act on PPARγ but which lacks the intrinsic cyclopentenone structure found in 15dPGJ₂, down-regulated CXCR4 substantially less potently than 15dPGJ₂. The cyclopentenone grouping is known to inhibit the activity of NFκB. Consistent with an additional role for NFκB, we found that the cyclopentenone prostaglandin PGA₂ and cyclopentenone itself could also down-regulate CXCR4. Immunolocalization studies showed that the cellular context was sufficient to trigger a focal nuclear pattern of NFκB p50 and that 15dPGJ₂ interfered with this p50 nuclear localization. These data suggest that 15dPGJ₂ can down-regulate CXCR4 on cancer cells through both PPARγ and NFκB. 15dPGJ₂, present within the tumor microenvironment, may act to down-regulate CXCR4 and impact upon the overall process of tumor expansion.