Mitochondrial DNA (mtDNA) mutations occur with high frequency in a variety of human tumors but the functional consequences of such mutations are unknown. The overall goal of our proposal is to understand how mtDNA mutations affect the malignant potential of cancer cells. We hypothesize that mtDNA mutations enhance the survival and proliferation while decreasing apoptosis of those tumors cells that happen to acquire them. We further propose that mtDNA mutations increase the mitochondrial production of reactive oxygen species (ROS) and that this increased ROS production is mitogenic, enhancing proliferation and decreasing apoptosis. Preliminary data from our lab shows that one such mtDNA mutation is indeed capable of enhancing the growth of human prostate cancer xenografts. In order to test this hypothesis 3 specific aims are proposed. First we will generate the laboratory constructs required to test the hypothesis. Specifically, we will create cytoplasmic hybrids (cybrids) that combine the nucleus of well-characterized prostate cancer cell lines with cytoplasm (and therefore mitochondria) containing either mutant or wild type mtDNA. Second, we will determine whether specific mutations affect the malignant phenotype, measuring cellular proliferation, apoptosis, cell cycle progression and tumorigenesis. Finally, we will determine the role of ROS in the observed phenotypic alterations, establishing whether ROS are a functional intermediate between mtDNA mutation and enhanced tumor growth. The accomplishment of these aims will allow us to determine whether mtDNA mutations enhance the malignant phenotype and whether such an alteration is due to increased ROS. In addition, we will generate cells, tumors and animal models that will allow the future study of the role of mtDNA in cancer by other investigators and aid in the pre-clinical screening of potential anti-neoplastics directed at tumors that harbor mtDNA mutations.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA096994-05
Application #
7116322
Study Section
Special Emphasis Panel (ZRG1-REB (01))
Program Officer
Okano, Paul
Project Start
2002-08-01
Project End
2008-07-31
Budget Start
2006-08-01
Budget End
2008-07-31
Support Year
5
Fiscal Year
2006
Total Cost
$241,430
Indirect Cost
Name
Emory University
Department
Urology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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