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.
- Antioxidant responsive element
- Prostaglandin E2