Peroxisome proliferator activated receptor (
PPAR) gamma is a
nuclear receptor involved primarily in
lipid and
glucose metabolism.
PPARgamma is also expressed in several
cancer types, and has been suggested to play a role in
tumor progression.
PPARgamma agonists have been shown to reduce the growth of
colorectal carcinoma cells in culture and in xenograft models. Furthermore, the
PPARgamma agonist
thiazolidinedione has been shown to reduce
metastasis in a murine model of
rectal cancer. Since the
chemokine receptor CXCR4 has emerged as an important player in
tumorigenesis, particularly in the process of
metastasis, we sought to determine if
PPARgamma agonists might act in part by reducing CXCR4 expression. We found that
rosiglitazone, a
thiazolidinedione PPARgamma agonist used primarily in the treatment of
type 2 diabetes, significantly reduced cell-surface expression of CXCR4
protein on HT-29 human
colorectal carcinoma cells. This effect occurred at concentrations as low as 1 nM, and was first evident after 8 h of drug exposure. CXCR4
mRNA was also down-regulated
after treatment with
rosiglitazone, indicating that the effect occurs at the level of transcription. Four other
thiazolidinedione compounds (
ciglitazone,
pioglitazone,
troglitazone, and MCC555) also significantly reduced CXCR4 expression. To confirm the involvement of
PPARgamma in
thiazolidinedione-induced CXCR4 down-regulation, we used
PPARgamma antagonists
GW9662 and
T0070907, both of which completely blocked the effect of
rosiglitazone on CXCR4 expression. Furthermore, HT-29 cells in which
PPARgamma expression was reduced using
shRNA were less responsive to
rosiglitazone. In conclusion, we have shown that
thiazolidinedione compounds reduce CXCR4
mRNA and
cell-surface protein expression in a
PPARgamma-dependent manner.