Positive and negative regulation of prostaglandin E2 biosynthesis in human colorectal carcinoma cells by cancer chemopreventive agents

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 (MGSTI-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-butylhydroquitione (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 MGSTI-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-Ibeta-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. (C) 2003 Published by Elsevier Science Inc.