Prostaglandin E(2) (
PGE(2)), a major
cyclooxygenase (COX-2) metabolite, plays important roles in
tumor biology and its functions are mediated through one or more of its receptors EP1, EP2, EP3, and EP4. We have shown that the matrix
glycoprotein fibronectin stimulates lung
carcinoma cell proliferation via induction of COX-2 expression with subsequent
PGE(2) protein biosynthesis.
Ligands of
peroxisome proliferator-activated receptor gamma (
PPARgamma) inhibited this effect and induced cellular apoptosis. Here, we explore the role of the
PGE(2) receptor EP2 in this process and whether the inhibition observed with
PPARgamma ligands is related to effects on this receptor. We found that human
non-small cell lung carcinoma cell lines (H1838 and H2106) express EP2 receptors, and that the inhibition of cell growth by
PPARgamma ligands (
GW1929,
PGJ2,
ciglitazone,
troglitazone, and
rosiglitazone [also known as
BRL49653]) was associated with a significant decrease in EP2
mRNA and
protein levels. The inhibitory effects of
BRL49653 and
ciglitazone, but not
PGJ2, were reversed by a specific
PPARgamma antagonist
GW9662, suggesting the involvement of
PPARgamma-dependent and -independent mechanisms.
PPARgamma ligand treatment was associated with phosphorylation of extracellular regulated
kinase (Erk), and inhibition of EP2 receptor expression by
PPARgamma ligands was prevented by PD98095, an inhibitor of the
MEK-1/Erk pathway.
Butaprost, an EP2 agonist, like exogenous
PGE(2) (dmPGE(2)), increased lung
carcinoma cell growth, however,
GW1929 and
troglitazone blocked their effects. Our studies reveal a novel role for EP2 in mediating the proliferative effects of
PGE(2) on lung
carcinoma cells.
PPARgamma ligands inhibit human lung
carcinoma cell growth by decreasing the expression of EP2 receptors through Erk signaling and
PPARgamma-dependent and -independent pathways.