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 PGE(2),
PGA(2),
PGD(2), PGJ(2) and 15dPGJ(2) each down-regulates
CXCR4 receptor expression on human
colorectal carcinoma cells to differing degrees. The most potent of these were
PGD(2) and its metabolites PGJ(2) and 15dPGJ(2). Down-regulation was most rapid with the end-product 15dPGJ(2) and was accompanied by a marked reduction in CXCR4
mRNA. 15dPGJ(2) is known to be a
ligand for the
nuclear receptor PPARgamma. Down-regulation of CXCR4 was also observed with the
PPARgamma agonist
rosiglitazone, while 15dPGJ(2)-induced CXCR4 down-regulation was substantially diminished by the
PPARgamma antagonists
GW9662 and
T0070907. These data support the involvement of
PPARgamma. However, the 15dPGJ(2) analogue CAY10410, which can act on
PPARgamma but which lacks the intrinsic
cyclopentenone structure found in 15dPGJ(2), down-regulated CXCR4 substantially less potently than 15dPGJ(2). The
cyclopentenone grouping is known to inhibit the activity of NFkappaB. Consistent with an additional role for NFkappaB, we found that the
cyclopentenone prostaglandin PGA(2) and
cyclopentenone itself could also down-regulate CXCR4. Immunolocalization studies showed that the cellular context was sufficient to trigger a focal nuclear pattern of NFkappaB p50 and that 15dPGJ(2) interfered with this p50 nuclear localization. These data suggest that 15dPGJ(2) can down-regulate CXCR4 on
cancer cells through both
PPARgamma and NFkappaB. 15dPGJ(2), present within the tumor microenvironment, may act to down-regulate CXCR4 and impact upon the overall process of
tumor expansion.