Epithelial Cell-specific Deletion of Microsomal Prostaglandin E Synthase-1 Does Not Influence Colon Tumor Development in Mice

Abstract

Activation of the COX-2/microsomal prostaglandin E synthase-1 (mPGES-1)/prostaglandin E 2 (PGE 2 ) signaling axis is a hallmark of many cancers, including colorectal cancer, prompting the implementation of prevention strategies targeting COX-2 activity. We have previously shown that targeting the downstream terminal PGE 2 synthase, mPGES-1 (Ptges), specifically reduces inducible PGE 2 formation without disrupting synthesis of other essential prostanoids, thereby conferring dramatic cancer protection against colon carcinogenesis in multiple mouse models. In order to accelerate its development as a viable drug target, and to better understand the mechanisms by which PGE 2 influences colon carcinogenesis, we recently developed a conditional Ptges knockout mouse model (cKO). To evaluate the functional role of Ptges directly within the colonic epithelia, cKO mice were crossed with carbonic anhydrase 1 (Car1)-Cre mice (cKO.Car1), and colon tumors were induced using the azoxymethane/dextran sodium sulfate protocol. Unexpectedly, epithelial-specific blockade of Ptges failed to protect mice against colon tumor development. Further studies using the cKO mouse model will be necessary to pinpoint the cell type-specific location of mPGES-1 and its control of inducible PGE 2 formation that drives tumor formation in the colon.

Prostaglandin E2 in the Tumor Microenvironment, a Convoluted Affair Mediated by EP Receptors 2 and 4

“…In NSCLC cell lines, for example, IL-4 inhibited the formation of PGE2 predominantly via a decrease in COX2 expression, whereas the expression of mPGES1 was unaffected (Cui et al, 2006). Nakanishi and Rosenberg (2021) have published a body of work focusing on the effects of mPGES-1 activity in colon cancer. Using genetic and carcinogeninduced colon cancer in vivo models, they were able to show that the global genetic deletion of mPGES-1 effectively suppresses intestinal tumorigenesis.…”