Abstract C76: Mechanistic implications of advanced glycation end-products to prostate cancer and racial disparity

Abstract

Poor diet, low income, obesity and a lack of exercise are established lifestyle factors that are known to increase cancer burden and are often more prevalent in African American communities. As our understanding of tumor biology advances, it is becoming increasingly clear that these inter-related lifestyle factors have distinct molecular consequences on the biological make-up of tumors, altering cell signaling events and gene expression profiles to contribute to cancer disparity outcomes such as its earlier development or its progression to more aggressive disease. Sparse information exists about the genetic and biological factors that contribute to differential cancer survival and mortality rates observed in minority populations. A greater understanding of the interplay between risk factors and the molecular mechanisms associated with cancer disparity will significantly impact minority health. Advanced glycation end products (AGEs) are reactive metabolites produced as a by-product of sugar metabolism. Failure to remove these highly reactive metabolites can lead to protein damage, aberrant cell signaling, increased stress responses, and decreased genetic fidelity. Critically, AGE accumulation is also directly affected by our lifestyle choices such as poor diet, low income, obesity and a lack of exercise. We recently reported a potential mechanistic link between AGEs and prostate cancer which may provide a molecular consequence of our lifestyle choices that can directly impact tumor biology and contribute to cancer disparity. We 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. Further mechanistic studies in immortalized prostate cancer cell lines show that AGE treatment increases the expression of the receptor for AGEs (RAGE) to activate cancer-associated signaling cascades. Loss of function studies show that AGE mediated increases in cancer associated processes was dependent upon RAGE expression. Significantly, we show that AGEs are secreted into the tumor microenvironment by cancer cells and may function as signaling molecules to promote immune cell recruitment. These data implicate the AGE-RAGE signaling axis as a potential biological mechanism promoting prostate cancer and 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: Danzell M. Smith, Dion Foster, Van Phan, Victoria J. Findlay, Lourdes M. Nogueira, Laura Spruill, Mahtabuddin Ahmed, Judith D. Salley, Marvella E. Ford, David P. Turner. Mechanistic implications of advanced glycation end-products to prostate cancer and racial disparity. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr C76.