Abstract 5581: Advanced glycation end-products are increased in prostate cancer and may promote racial disparity

Abstract

Abstract African American cancer patients are more likely to die of their disease than their European counterparts. Our research has identified a potential mechanistic link between carbohydrate derived metabolites and cancer associated pathways which may provide a biological consequence of the socioeconomic and environmental factors that are known to drive cancer health disparity. Glycation is the non-enzymatic glycosylation of sugar moieties to biological macromolecules such as protein and DNA which produces reactive metabolites known as advanced glycation end products (AGE's). AGE's accumulate in our tissues as we grow older and drive many of the complications associated with diseases displaying health disparity including diabetes, metabolic syndrome, Alzheimer's, and heart disease. Low income, obesity and an inactive/sedentary lifestyle are established factors driving cancer health disparity. Significantly, apart from their production during normal metabolism, AGE's are also formed through the ingestion of food and by external environmental factors such as lack of exercise. AGE content in the Western Diet has consistently increased over the last 50 years due to increased consumption of sugar laden and cheap processed/manufactured foods which are high in reactive AGE metabolites and can promote obesity. We therefore examined circulating and intra-tumoral AGE metabolite levels in clinical specimens and identified a race specific, tumor dependent pattern of accumulation in prostate cancer serum and tumor. In mouse xenograft models, AGE accumulation was highest in the more aggressive tumors. One way AGE's mediate their deleterious effects is by functioning as ligand for the trans-membrane receptor for AGE (RAGE). In diabetes and other diseases, the AGE-RAGE signaling axis is a pro-inflammatory pathway leading to the upregulation of pro-inflammtory cytokines through increased NFkB activation. Higher AGE levels in African American prostate tumors corresponded with higher RAGE expression and increased NFkB transcriptional activity. In immortalized prostate cancer cell lines AGE treatment increased cancer associated processes and RAGE expression levels. Loss of function studies show that AGE mediated increases in cancer associated processes was dependent upon RAGE expression. These data implicate the AGE-RAGE signaling axis as a potential biological mechanism promoting prostate cancer and indicate that increased AGE accumulation may represent a biological mechanism promoting prostate cancer disparity. AGE metabolites may have high potential impact as prognostic/diagnostic markers and/or as a novel area of potential therapeutic intervention to reduce cancer disparity. Citation Format: Katherine R. Walter, Dion Foster, Victoria Findlay, Lourdes Nogueira, Sadia Robinson, Emily Kistner-Griffin, Laura Spruill, Ryan Kelly, Mahtabuddin Ahmed, Judith Salley, Marvella Ford, David Turner. Advanced glycation end-products are increased in prostate cancer and may promote racial disparity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5581. doi:10.1158/1538-7445.AM2014-5581