Prostaglandin E2 stimulates progression-related gene expression in early colorectal adenoma cells

Abstract

Upregulation of cyclooxygenase-2 (COX-2) and prostaglandin-dependent vascularisation in small adenomatous polyps is an essential part of colon carcinogenesis. To study the underlying cellular mechanisms, LT97 and Caco2 human colorectal tumour cells not expressing endogenous COX-2 were exposed to 1 mM prostaglandin E 2 (PGE 2 ) in their medium. At 30 min after addition, expression of c-fos was stimulated 5-fold and 1.3-fold, respectively, depending on the activation of both extracellular signal-regulated kinase and p38. The amount of c-jun in nuclear extracts was increased 20% in LT97 cells. Expression of COX-2 was upregulated 1.7-fold in LT97 cells and 1.5-fold in Caco2 2 h after prostaglandin (PG) addition by a p38-mediated pathway. The known PGE 2 target gene vascular endothelial growth factor (VEGF) was not modulated. Effects of sustained PGE 2 production were studied in VACO235 cells that have high endogenous COX-2 and in LT97 cells infected with an adenovirus expressing COX-2. Prostaglandin E 2 secretion into the medium was 1 -2 nM and 250 pM, respectively. Expression of both VEGF and c-fos was high in VACO235 cells. In LT97 cells, COX-2 upregulated c-fos expression and c-jun content in nuclear extracts 1.7-and 1.2-fold, respectively, in a PG-dependent way. This shows that exogenous PGE 2 as well as COX-2 overexpression affect signalling and gene expression in a way that enhances tumour progression. British Journal of Cancer (2006) Upregulation of cyclooxygenase-2 (COX-2) expression in early adenomas is an essential prerequisite of colorectal carcinogenesis. It causes elevated levels of prostaglandins (PGs) in the tissue and PG-dependent neovascularisation (Eberhart et al, 1994). Adenomatous polyps regress under therapy with non-steroidal anti-inflammatory drugs whose main cellular target is COX-2 (DuBois et al, 1996). Mice carrying a hereditary mutation in the APC gene (min-mice or transgenic DAPC-mice; (de Wind et al, 1998) develop a multitude of intestinal polyps in a COX-2 and prostaglandin E 2 (PGE 2 )-receptor-dependent way (Sonoshita et al, 2001;Seno et al, 2002;Sunayama et al, 2002). Immunohistochemical analysis of tissue sections shows that much of the COX-2 is located in connective tissue but not in the epithelial compartment of the polyps. In the pathology of human colorectal cancer, COX-2 plays a similar role and has become the main target of chemoprevention in high-risk patients (DuBois et al, 1996;Gupta and Dubois, 2001). As in the mouse models, COX-2 is mainly located in the connective tissue of human adenomatous polyps.This raises the question whether PGs produced in the microenvironment (fibroblasts, endothelial cells or macrophages) can in turn affect early premalignant cells and trigger expression of tumour-associated genes. To answer these questions we have established the human colonic adenoma cell line LT97 from microadenomas of a polyposis patient that do not yet express COX-2 or produce PGE 2 (Richter et al, 2001). Tumour-promoting bile acids have been shown to induce expression of ...

Green Tea Extracts for the Prevention of Metachronous Colorectal Adenomas: A Pilot Study

“…Clinical studies also showed that the ingestion of green tea extract inhibited the COX-dependent arachidonic acid metabolism and decreased the level of prostaglandin E 2 in colorectal mucosa (28,29). Thus, we think that GTE prevented metachronous colonic adenoma, in part, by interfering with the COX-2/prostaglandin E 2 axis in the mucosa because the aberrant activation of this axis is an essential prerequisite to the early development of adenoma (30,31). In addition, there is increasing evidence for a complex positive feedback circuitry between epidermal growth factor receptor -related signaling, COX-2, and prostaglandin E 2 , and this seems to be associated with the early stage of colonic tumorigenesis (30)(31)(32)(33).…”

“…Thus, we think that GTE prevented metachronous colonic adenoma, in part, by interfering with the COX-2/prostaglandin E 2 axis in the mucosa because the aberrant activation of this axis is an essential prerequisite to the early development of adenoma (30,31). In addition, there is increasing evidence for a complex positive feedback circuitry between epidermal growth factor receptor -related signaling, COX-2, and prostaglandin E 2 , and this seems to be associated with the early stage of colonic tumorigenesis (30)(31)(32)(33). The insulin-like growth factor/insulin-like growth factor-I receptor system is also involved in the COX-2/prostaglandin E 2 axis and, therefore, plays a role in colorectal carcinogenesis (34,35).…”

EP4 and EP2 Receptor Subtypes Involved in Colonic Secretion in Rat

“…In recent years, there has been a tremendous surge in interest and focus on EP receptor subtypes and their relation to colorectal cancer [7,[30][31][32][33][34][35][36], its enhancement by angiogenesis [37][38][39][40], and its spread as well as a possible treatment for remission with EP receptor specific agonists and antagonists against progression of the disease or amelioration of metastasis [41][42][43]. Prostanoids are also involved in other colon diseases such as colitis [44][45][46][47] and polyposis [48,49].…”

Anticancer Activity and Nutritional Value of Extracts of the Seed of Glinus lotoides

“…It was also reported that -3 fatty acids present in dietary meal inhibit oxidative metabolism of arachidonic acid by the cyclooxygenase (COX) pathway responsible for prostaglandin synthesis (36). Studies have indicated that prostaglandin synthesis inhibitors prevent colon carcinogenesis (37). Recently Suzuki et al showed that consumption of Catalpa ovata seed oil, which is rich in conjugated linolenic acid, suppresses the development of colonic aberrant crypt foci induced by azoxymethane in rats (35).…”