224 MOLECULAR CONSEQUENCES OF MITOCHONDRIAL DNA MUTATIONS IN PROSTATE CANCER

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research II1 Apr 2010224 MOLECULAR CONSEQUENCES OF MITOCHONDRIAL DNA MUTATIONS IN PROSTATE CANCER Courtney Plattner, Carrie Sun, Takara Scott, Rebecca Arnold, and John Petros Courtney PlattnerCourtney Plattner More articles by this author , Carrie SunCarrie Sun More articles by this author , Takara ScottTakara Scott More articles by this author , Rebecca ArnoldRebecca Arnold More articles by this author , and John PetrosJohn Petros More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.282AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES It is now known that mutations in the mitochondrial DNA (mtDNA) are associated with prostate cancer. These mutations can be either inherited or somatically acquired and may contribute to the racial disparities in prostate cancer, with blacks exhibiting a higher incidence of inherited mtDNA mutations than whites. The objective of this study was to identify molecular consequences of mtDNA mutations in prostate cancer that may contribute to the malignant phenotype. By understanding these specific molecular alterations it is hoped that novel therapeutic agents may be developed targeted at this pathway, perhaps based on genetic testing. METHODS We introduced a single mtDNA base mutation that alters an amino acid into a human prostate cancer cell line. The ATP6 gene mutation T8993G results in the amino acid substitution Leu156Arg and hyperpolarizes the inner mitochondrial membrane. These cells (along with their wild type counterparts) were studied in vivo as nude mouse xenografts and in vivo for cell and molecular biologic alterations. Quantitative western analysis was used to measure changes in protein expression that resulted as a consequence of the mutation. Superoxide anion and hydrogen peroxide levels were measured by fluorescence using reagents dihydroethidium (DHE) and dichlorofluorescein (DCF) respectively. RESULTS The introduction of the 8993 mtDNA mutation increases tumor growth rates in nude mice and reactive oxygen production in these tumors. In the mutant cell lines there was a significant increase in the phosphorylated (active) form of focal adhesion kinase (pFAK) and fibroblast growth factor-1 (FGF1) compared to wild type prostate cancer cells. Cancer cells had significantly less PEDF (SERPINF1) protein than wild type cells. The mtDNA mutation also caused increased reactive oxygen, both superoxide and peroxide. CONCLUSIONS Mutations of the mitochondrial genome are common in clinical prostate cancer and may exert their carcinogenic effects via production of mitochondrially generated reactive oxygen. The T8993G mtDNA mutation causes prostate cancer cells to generate more ROS, and induces a coordinated change in three key cancer related proteins favoring the malignant phenotype. This suggests the potential future clinical translation of prostate cancer pharmaceuticals directed against mitochondrial ROS and/or specific proteins (FGF, pFAK, PEDF) based on mtDNA genotyping of patients or their tumors. Atlanta, GA© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e88 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Courtney Plattner More articles by this author Carrie Sun More articles by this author Takara Scott More articles by this author Rebecca Arnold More articles by this author John Petros More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...