Prostaglandin E2 enhances intestinal adenoma growth via activation of the Ras-mitogen-activated protein kinase cascade.
A large body of clinical, genetic, and biochemical evidence indicates that cyclooxygenase-2 (COX-2), a key enzyme for prostanoid biosynthesis, contributes to the promotion of colorectal cancer. COX-2-derived prostaglandin E2 (PGE2) is the most abundant prostaglandin found in several gastrointestinal malignancies. Although PGE2 enhances intestinal adenoma growth in Apcmin mice, the mechanism(s) by which it accelerates tumor growth is not completely understood. Here we investigated how PGE2 promotes intestinal tumor growth and the signaling pathways responsible for its effects. We observed that PGE2 treatment leads to increased epithelial cell proliferation and induces COX-2 expression in intestinal adenomas. Furthermore, we show that PGE2 regulation of COX-2 expression is mediated by activation of a Ras-mitogen-activated protein kinase signaling cascade. One intriguing finding is that COX-2-derived PGE2 mimics the effects of constitutively active Ras through a self-amplifying loop that allows for a distinct growth advantage.
Wang
Dingzhi
D
Departments of Medicine, Pediatrics, Cancer Biology, and Cell and Developmental and Biology, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
Buchanan
F Gregory
FG
Wang
Haibin
H
Dey
Sudhansu K
SK
DuBois
Raymond N
RN
D000236:Adenoma / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D049109:Cell Proliferation; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D017491:Genes, APC / Q000502:physiology; D007414:Intestinal Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000378:metabolism*
D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins; D015232:Dinoprostone