Colorectal cancer is the second most common cause of cancer death in the United States. An increase in reactive oxygen species (ROS) generated from oxidative stress is generally associated with abnormal cancer cell growth and reflects a disruption of redox homeostasis. Manganese superoxide dismutase (SOD2) and glutathione peroxidase 4 (Gpx4) are two of the most important antioxidant defense enzymes that protect cells against oxidative stress. Interestingly, we have recently demonstrated that n-3 polyunsaturated fatty acids (PUFA) enhance apoptosis, a useful marker of colorectal cancer risk, in colonocytes by enhancing phospholipid oxidation. In order to elucidate the mechanisms regulating oxidative stress-induced apoptosis in vivo, we fed SOD2het, Gpx4het and Gpx4 over-expressing (Gpx4TG) transgenic mouse models diets containing either n-3 or n-6 PUFA (control). Animals were fed diets containing either 15% corn oil by weight (CO, enriched in n-6 PUFA) or 3.5% CO + 11.5% fish oil (FO, enriched in n-3 PUFA) for 4 wk. Apoptotic cells in the distal colon were enumerated in situ. Relative to their respective wild type siblings, Gpx4het and SOD2het mice had significantly (P<0.05) enhanced levels of colonocyte apoptosis, 63% and 20%, respectively. In contrast, apoptosis in Gpx4TG mice was significantly (P<0.05) reduced by 16% compared to wild type siblings. FO vs CO feeding further increased (P<0.05) apoptosis in Gpx4het and SOD2het mice by 42% and 18%, respectively. In addition, n-3 PUFA elevated apoptosis in Gpx4TG mice back to a level comparable with wild type (control) siblings. These data indicate that dietary and/or genetic pre-deposition to oxidative stress facilitates apoptosis in the colon, thereby reducing colon cancer risk. Supported in part by NIH grants CA59034, CA129444, P30ES09106, and USDA 2008-34402-19195, “Designing Foods for Health” through the Vegetable & Fruit Improvement Center.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 955.