Oxidative stress-induced cellular survival pathways in prostate cancer

Loma Linda University, Loma Linda CA

Investigators

Linked publications & trials

Abstract

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