Prostate cancer is the most common form of cancer in men and the second leading cause of cancer deaths in men in the United States. The growth of prostate cancer is initially androgen dependent. Androgen ablation, the main therapy for progressive prostate cancer, causes regression of androgen-dependent cancers. However, many men eventually die of recurrent, androgen-independent prostate cancer, a lethal form that inevitably progresses and metastasizes. Mutation of nuclear or mitochondrial DNA (mtDNA) may allow prostate cancer to survive in the absence (or low concentration) of androgen; however, the basic mechanisms that determine the progression of prostate cancer to an androgen-independent form are not completely understood. Mitochondria are now considered to be a key organelle regulating apoptosis. We previously showed that depletion of mtDNA reduced apoptosis induced by specific mediators. Several characteristics associated with metastatic competence, such as invasion and overexpression of the tumor-specific regulators cathepsin L and transforming growth factor-beta, can also be induced by depletion of mtDNA. Thus mutation or loss of mtDNA could contribute to cancer development by inhibiting apoptosis or inducing metastatic competence. Our preliminary results indicate that androgen ablation in mouse model system greatly reduced the amount of normal mtDNA and increased the amount of large deletion mutant mtDNA. Cells with a high proportion of large deletion mutant mtDNA lack some or most mtDNA-encoded proteins and therefore might show characteristics similar to those of cells with depleted mtDNA. Strikingly, depletion of mtDNA from androgen-sensitive LNCaP resulted in a loss of responsiveness to androgen and the development of clones that could proliferate in the absence of androgen. Reconstitution of normal mtDNA to mtDNA depleted clone reversed androgen sensitivity. The accumulation of large deletion mutant mtDNA may thus play a role in the development of androgen independence and progression of prostate cancers. This application will explore the role of accumulation of large deletion mutant mtDNA as a potential cause of prostate cancer progression. In this proposal, we will investigate whether androgen ablation accumulates the proportion of deletion mutant mtDNA in prostate cancers by analyzing the deletion mutant mtDNA and how androgen ablation accumulates deletion mutant mtDNA by investigating the roles of reactive oxygen species. We will also investigate whether and how the increase in deletion mutant mtDNA abrogates androgen-sensitivity in prostate cancers by establishing several cybrids with nuclear DNA from androgen-sensitive prostate cancer cells with mtDNA from several prostate cancer cells. A confirmation of our hypothesis and an understanding of the underlying mechanisms could lead to novel approaches for prevention or therapy of prostate cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Metabolic Pathology Study Section (MEP)
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Woodhouse, Elizabeth
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University of Arkansas for Medical Sciences
Schools of Medicine
Little Rock
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