title: Positive and negative regulation of prostaglandin E2 biosynthesis in human colorectal carcinoma cells by cancer chemopreventive agents.
abstract: Increased production of prostaglandin E(2) (PGE(2)) by the combined activities of cyclooxygenase-2 (COX-2) and microsomal glutathione S-transferase 1-like 1 (MGST1-L1) enhances the progression of colorectal cancer. To assess how chemopreventive agents influence colon tumorigenesis, the modulation of PGE(2) production by indolo[3,2-b]carbazole (ICZ), beta-naphthoflavone (beta-NF), and tert-butylhydroquinone (tBHQ), as well as the nonsteroidal anti-inflammatory drug Piroxicam, has been studied in the human HCA-7 colon carcinoma cell line. We have found that these xenobiotics both down-regulate and up-regulate the expression of COX-2 and MGST1-L1. They can also either inhibit or stimulate PGE(2) synthesis. COX-2 mRNA levels were increased significantly by those compounds that activate transcription through the xenobiotic responsive element (XRE) and/or the antioxidant responsive element (ARE). A possible ARE enhancer was identified in the COX-2 promoter, and reporter gene experiments demonstrated that tBHQ induction of a transgene driven by the 5'-flanking region of COX-2 was increased by co-transfection with an expression vector for the Nrf2 transcription factor. By contrast, only compounds such as ICZ and beta-NF which activate the XRE increased the mRNA levels of MGST1-L1. While the ARE-specific inducer tBHQ did not modulate the basal expression of MGST1-L1, it was found to act as an antagonist of interleukin-1 beta-stimulated MGST1-L1 overexpression. Changes in COX-2 and MGST1-L1 expression were not always coincident with a corresponding change in PGE(2) production by human colon carcinoma cells. Importantly, dietary compounds can modulate PGE(2) biosynthesis, and this is likely to influence colon tumorigenesis.
authors.affiliation: Biomedical Research Centre, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, Scotland, UK. Philip.Sherratt@spcorp.com
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Sherratt
authors.forename: Lesley I
authors.initials: LI
authors.lastname: McLellan
authors.forename: John D
authors.initials: JD
authors.lastname: Hayes
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D001483:Base Sequence; D002227:Carbazoles / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000473:pathology; D015179:Colorectal Neoplasms / Q000473:pathology; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000378:metabolism*; D004347:Drug Interactions; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D005982:Glutathione Transferase / Q000096:biosynthesis; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D010894:Piroxicam / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D014407:Tumor Cells, Cultured; D019324:beta-Naphthoflavone / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D002227:Carbazoles; D006873:Hydroquinones; D007211:Indoles; D007375:Interleukin-1; D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; D010894:Piroxicam; C075954:indolo(3,2-b)carbazole; D019324:beta-Naphthoflavone; C018855:2-tert-butylhydroquinone; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C122107:microsomal glutathione S-transferase-I; D005982:Glutathione Transferase; D015232:Dinoprostone