Prostaglandin E(2) (
PGE(2)) is a bioactive
lipid that mediates a wide range of physiologic effects and plays a central role in
inflammation and
cancer.
PGE(2) is generated from
arachidonic acid by the sequential actions of the COX and terminal synthases (PGES). Increased levels of COX-2, with a concomitant elevation of
PGE(2), are often found in
colorectal cancers (CRC), providing the rationale for the use of
COX-2 inhibitors for
chemoprevention. Despite their proven efficacy in
cancer prevention, however,
COX-2 inhibitors exhibit dose-dependent toxicities that are mediated in part by their nonspecific reduction of essential
prostanoids, thus limiting their chemopreventive benefit. To achieve enhanced specificity, recent efforts have been directed toward targeting the inducible terminal synthase in the production of
PGE(2), microsomal PGES (mPGES-1). In the present study, we show that genetic deletion of mPGES-1 affords significant protection against
carcinogen-induced
colon cancer. mPGES-1 gene deletion results in an about 80% decrease in
tumor multiplicity and up to a 90% reduction in
tumor load in the distal colon of
azoxymethane (AOM)-treated mice. Associated with the striking
cancer suppression, we have identified a critical role for
PGE(2) in the control of immunoregulatory cell expansion (FoxP3-positive regulatory T cells) within the colon-draining mesenteric lymph nodes, providing a potential mechanism by which suppression of
PGE(2) may protect against CRC. These results provide new insights into how
PGE(2) controls antitumor immunity.