Abstract 4477: Downregulation of ABCG2 expression in colitis and colon cancer: Relevance to iron overload, hemochromatosis and p53, and therapeutic use of carbidopa to reverse the downregulation

Abstract

Abstract The efflux pump ABCG2 is a part of cellular defense. In intestine it is located at the luminal side, and effluxes exogenous/endogenous dysplasia-promoting agents. Since cancer cells exposed to chemotherapeutics overexpress ABCG2 to remove these drugs, ABCG2 is considered a multidrug-resistance protein. However, its physiologic protective role in cancer initiation/progression has not received much attention. In numerous studies, ABCG2 is present in colon at lower levels in patients with colitis and chemotherapy-naïve colon cancer than in controls. We therefore hypothesized that the physiologic role of ABCG2 is to suppress colonic inflammation and colon cancer. To test this, we monitored Abcg2 expression in the intestinal tract in experimental and genetic mouse models of colon cancer and colitis. In normal mice, Abcg2 was expressed throughout the intestinal tract, jejunum being the site with maximal expression. Colon was positive for expression, but the expression was lower than in jejunum. Compared to control colon, Abcg2 was present at lower levels in colonic polyps from experimental and genetic models of colon cancer; the same trend was seen in normal and cancer cell lines of colonic origin. In line with human colitis studies, colons from colitis mouse models had lower expression of Abcg2 compared to control colon. The association of excess iron to colon cancer is well known, but it is not known if excess iron has any role in tumor-associated downregulation of ABCG2 in colon. We used Hfe-/- mice as a model for hemochromatosis, a genetic iron-overload disease, and exploited the ability of Abcg2 to export uric acid as a measure of Abcg2 function. Colons from Hfe-/- mice had lower expression of Abcg2 and higher accumulation of uric acid. This decrease in Abcg2 function indicated that excess iron, directly or indirectly, dictates Abcg2 expression in colon. To better understand this phenomenon, colon cells were treated with ferric ammonium citrate as an iron source. This in vitro iron-overload model demonstrated nuclear depletion of the tumor suppressor p53, and at the same time a decrease in Abcg2 expression. In addition, Abcg2 mRNA was undetectable in p53-null mouse embryonic mouse fibroblasts, suggesting that Abcg2 is a p53 target. Additional in vitro studies included treatment of normal and cancer colon cells with Carbidopa, a drug which was recently shown as an aryl hydrocarbon receptor agonist. Our studies showed that Carbidopa is a potent iron chelator and an inducer of ABCG2 expression. In summary, ABCG2 is silenced in colon cancer and colitis, and the decreased expression of p53 under these conditions might be responsible for the decreased ABCG2 expression. Carbidopa could be used to reduce cellular levels of iron and to reverse iron-induced downregulation of ABCG2 as a prevention/treatment strategy for colitis and colon cancer. Citation Format: Bojana Ristic, Sathish Sivaprakasam, Jiro Ogura, Vadivel Ganapathy. Downregulation of ABCG2 expression in colitis and colon cancer: Relevance to iron overload, hemochromatosis and p53, and therapeutic use of carbidopa to reverse the downregulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4477.