Prostate cancer (PCa) is the second highest cause of cancer-related deaths in men. African American/Black (AA/B) men are disproportionally impacted by PCa with a 60% higher incidence of disease and a 2-fold increase in mortality risk compared to European American (EA) men. There is an urgent need to elucidate the underlying biological changes that give rise to this disparity to develop inclusive diagnostic and predictive tests and tailored therapeutic treatments. Environmental factors (the exposome) are proposed to contribute to this disparity and can influence disease risk through gene-environment interactions, in which genotypes may influence the response to environmental exposure. A significant contributor to PCa mortality is diabetes incidence, which varies due to the exposome. The mechanisms involved in increased PCa mortality in men with diabetes are not clear but are proposed to arise from physiological changes caused by diabetes-associated metabolic alterations. A proposed mechanism for how these changes increase PCa mortality is through the production of the reactive electrophile methylglyoxal (MG). MG is a by-product of lipid, protein, and sugar metabolism and forms covalent adducts on DNA, RNA, and protein. These adducts, termed MG-advanced glycation end products (MG-AGEs) lead to DNA mutations and genomic instability, change RNA stability and translation, and alter protein stability and function. In addition, MG-AGEs bind and activate the receptor for AGEs (RAGE). To regulate MG and MG-AGEs, cells use glyoxalase 1 (GLO1) to detoxify MG and soluble RAGE (sRAGE) to sequester MG-AGEs and prevent RAGE activation. These components comprise the AGE/RAGE axis. To define the association of MG-AGEs, GLO1, RAGE, and sRAGE with PCa health disparities, we designed a clinical study of AA/B and EA men with and without PCa. We measured serum MG-AGEs using mass spectrometry, serum sRAGE using ELISA, and sequenced the GLO1 and AGER (gene encoding RAGE) loci in genomic DNA isolated from whole blood. We discovered that MG-AGEs, sRAGE, and GLO1 and AGER SNPs were significantly associated with PCa in AA/B men but not EA men. We also observed a significant difference between these components in AA/B and EA men without PCa. This led us to hypothesize that MG-AGEs, sRAGE, and GLO1 and AGER SNPs may have utility as biomarkers for PCa in AA/B men and that GLO1 SNPs may play a role in the accumulation of MG-AGEs, mutations, and PCa cell growth.

Sarah Shuck

City of Hope

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