Oxidative stress-induced cellular survival pathways in prostate cancer

流行病学研究表明，非裔美国人（AA）男性在临床上的发病率最高

Epidemiological studies demonstrate that African-American (AA) men have the highest incidence of clinically detected prostate cancer (PCa) in the world. AA men are diagnosed with advanced PCa at a significantly younger age, and their mortality is also significantly higher. Growing evidence points to high intake of dietary fat as an important exogenous risk factor in PCa development, particularly among AA men. High intake of dietary fat appears to contribute to PCa development by driving the production over time of: 1) molecules that enhance cell proliferation and angiogenesis, and influence inflammation; and 2) reactive oxygen species (ROS) that produce a state of augmented oxidative stress in the prostate. Prostate cells adapt to this environment by activating stress/survival signaling pathways that promote resistance to oxidative stressinduced death. A comprehensive molecular approach to understand the biological basis of the increased PCa incidence and mortality in AA men is critically needed to eliminate these disparities. Our long-term goal is to understand the biological basis of these disparities by studying oxidative stress-dependent cellular survival pathways activated in the prostate. The focus of this project is the lens epithelium-derived growth factor of 75 kilodaltons (LEDGF/p75), a transcription factor regulated by oxidative stress that is overexpressed in prostate tumors and promotes resistance to oxidative stress-induced cell death. Our hypothesis is that LEDGF/p75 promotes prostate cancer cell resistance to oxidative stress-induced death by activating a novel survival pathway involving stress genes controlling the cellular redox environment. The specific aims are designed to: (1) identify stress/redox genes regulated by LEDGF/p75 in prostate cancer cells; (2) demonstrate that stress/redox genes regulated by LEDGF/p75 have elevated expression in prostate cancer tissue and cells and promote resistance to oxidative stress-induced cell death; and (3) demonstrate that functional inactivation of LEDGF/p75 and specific stress/redox genes it regulates sensitizes PCa cells to oxidative stress-induced death. Experimental approaches include pathway-focused DMA microarray analysis, real-time PCR, transcription reporter assays, tissue microarray analysis, and RNA inhibition. The proposed work is innovative because it focuses on a novel pathway of PCa cell resistance to oxidative stress-induced death, mediated by LEDGF/p75, which could be ari important component of the molecular basis for the disparities in PCa incidence and mortality. These studies are highly relevant because they are likely to lead to the preclinical development of novel therapeutic strategies for advanced PCa targeting the LEDGF/p75-mediated survival pathway. They are also expected to yield valuable information that could be used for the design of community-participatory preventive interventions aimed at reducing the disparities in the incidence and mortality of PCa in the Inland Empire of Southern California.