Abstract C031: Regular physical activity can prevent the oncogenic effects of lifestyle-associated advanced glycation end products

Abstract

Advanced glycation end-products (AGEs), are reactive metabolites produced endogenously as a consequence of glucose metabolism. AGEs accumulate in tissues and organs as we grow older to promote multiple chronic disease phenotypes. AGE pathogenic effects are mediated through modification of protein function, genetic fidelity, stress responses and cellular signaling pathways. Critically, cancer disparity factors such as a sedentary lifestyle, obesity and an unhealthy diet are external influences that have been shown to contribute to the accumulation of AGEs. This research group examined circulating and tumor AGE levels in clinical specimens of prostate cancer and identified a race specific, tumor-dependent pattern of accumulation. AGE levels were highest in aggressive tumors, especially those from men with African ancestry. As our understanding of tumor biology advances, it is becoming increasingly clear that these lifestyle factors have distinct molecular consequences on the biologic make up of tumors, altering cell signaling events and gene expression profiles to contribute to cancer disparity outcomes such as earlier development or its progression to more aggressive disease. Increased AGE levels correlated with an up-regulation in the receptor for advanced glycation end products (RAGE) and activated NFkB. In a syngeneic sub-cutaneous prostate cancer mouse model, chronic consumption of AGE resulted in a 3-fold increase in tumor growth. Dietary-AGE mediated increases in tumor growth were accompanied by a cytoplasmic accumulation of AR, elevation in MYC, RAGE, and AGE as well as increased cell proliferation. Given the links between lifestyle and AGEs we examined the effects of regular physical activity on AGE induced tumor growth in our syngeneic sub-cutaneous dietary-AGE prostate cancer model. Mice exposed to physical activity for 1 hour, 5 days per week showed a significant decrease in AGE induced tumor growth. We also examined the effects of dietary-AGEs on tumor progression using the FVB-Tg(C3-1-TAg)cJeg/JegJ (C3-Tag) transgenic spontaneous prostate cancer mouse model. This model progresses to low grade prostate intraepithelial neoplasia (PIN) at 24 weeks. However, chronic consumption of AGE resulted in increased progression towards moderate to high grade PIN at this same time point. When regular physical activity was introduced, we observed delayed progression of PIN in both dietary groups, but most significantly in the high AGE fed mice. These studies support the concept that AGEs represent a biological consequence of the socioeconomic and environmental factors that promote cancer disparity, which may be at least in part reversed via physical activity. This may have the greatest impact for African American patients who tend to have poorer survival, and where a lack of physical activity, poor diet, and high obesity rates are more prevalent. Citation Format: Bradley A Krisanits, Pamela M Woods, Dion Foster, Lourdes M Nogueira, Laura Spruill, Marvella E Ford, Victoria J Findlay, David P Turner. Regular physical activity can prevent the oncogenic effects of lifestyle-associated advanced glycation end products [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C031.