15-Deoxy-Δ12,14-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.