Mitochondrial DNA and Prostate Cancer in African American

描述(申请人提供)：线粒体在细胞增殖、细胞信号传递和细胞凋亡中起核心作用。线粒体含有它们自己的DNA(MtDNA)。线粒体DNA是人类起源和种族的决定因素。人类线粒体DNA是一个非常小(16,569个核苷酸)的基因组。线粒体基因组的整个蛋白质编码能力专门用于生产13个蛋白质亚基。这13个蛋白质组成了不同的亚基，组成了四个氧化磷酸化(OXPHOS)复合体，对能量(ATP)的产生和其他线粒体功能至关重要。非裔美国人男性(AAM)的前列腺癌发病率最高，发病年龄较早，确诊时肿瘤分级较高，转移率和死亡率高于高加索美国男性(CAM)。前列腺癌的种族多样性背后的遗传机制(S)还不是很清楚。我们的研究表明，在AAM中，线粒体DNA含量降低在前列腺癌的发生中起着重要作用。检测AAM和CAM获取的白细胞(WBC)和前列腺癌组织中线粒体DNA的拷贝数。我们的初步研究表明，AAM和CAM的WBC中含有相似数量的mtDNA(拷贝数)。然而，当调整了年龄、Gleason分级和PSA(前列腺特异性抗原)后，AAM的前列腺癌的mtDNA含量比CAM肿瘤少6倍。我们的初步数据表明，编码线粒体DNA聚合酶伽马(POLG1)的核基因突变会导致mtDNA耗尽，并在体外增加癌细胞的致瘤潜力。这些研究表明，线粒体DNA动态平衡在肿瘤的发生中起着重要作用。基于这些观察，我们推测线粒体DNA含量降低通过显著改变线粒体OXPHOS在AAM的前列腺癌发生中起关键作用。目的1：确定AAM前列腺癌POLG1突变谱是否不同于CAM的POLG1突变谱。鉴定AAM原发前列腺肿瘤中POLG1基因的独特突变，并确定其在线粒体DNA耗竭、OXPHOS活性和细胞凋亡中的功能意义。目的：研究突变体POLG1诱导的线粒体DNA缺失在体外和小鼠异种移植模型中对前列腺癌发生的影响。提出的前列腺细胞线粒体DNA缺失的研究具有显著的潜力，可以增强我们对非裔美国人人群中前列腺肿瘤发生的了解。该提案涉及PAR-09-160要求在癌症健康差异的基础癌症研究中提供探索性拨款的两个关键目标(R21)。这些目标包括：1)开发“旨在研究癌症差异的新细胞培养模型/系统”；2)探索由于线粒体DNA含量的“遗传差异”而导致的非裔美国人患前列腺癌的易感性。

DESCRIPTION (provided by applicant): Mitochondria play a central role in cell proliferation, cell signaling and apoptosis. Mitochondria contain their own DNA (mtDNA). mtDNA serves as a determinant of human origin and ethnicity. Human mtDNA is a very small (16,569 bp) genome. The entire protein coding capacity of the mitochondrial genome is dedicated to the production of 13 protein subunits. These 13 proteins constitute various subunits that make up four oxidative phosphorylation (OXPHOS) complexes essential for energy (ATP) production and other mitochondrial function. African-American men (AAM) have the highest rate of prostate cancer, develop prostate cancer at an early age, present with a higher tumor grade at time of diagnosis, and have a higher rate of metastasis and mortality than Caucasian American men (CAM). The genetic mechanism(s) underlying this racial diversity in prostate cancer is not well understood. Our studies demonstrate that in AAM reduced mtDNA content plays an important role in prostate carcinogenesis. We measured the mtDNA copy number in white blood cells (WBC) and prostate tumor obtained from AAM and CAM. Our preliminary studies suggest that WBC of both AAM and CAM contained similar amount of mtDNA (copy number). However, when adjusted for age, Gleason grade and PSA (prostate specific antigen) the prostate tumors of AAM contained >6 times less mtDNA than CAM tumors. Our preliminary data suggest that mutations in nuclear gene encoding mitochondrial DNA polymerase gamma (POLG1) induce depletion of mtDNA and increase tumorigenic potential of cancer cells in vitro. These studies suggest that mtDNA homeostasis must play an important role in carcinogenesis. Based on these observations we hypothesize that reduced mtDNA content plays a critical role in prostate tumorigenesis in AAM by significantly altering the mitochondrial OXPHOS. AIM 1: Determine whether mutational spectrum of POLG1 in AAM prostate tumors differs from POLG1 mutational spectrum of CAM. Identify distinctive mutations in POLG1 gene in primary prostate tumors of AAM and determine its functional significance on mtDNA depletion, OXPHOS activity and apoptosis. AIM 2: Determine the consequences of mutant POLG1 induced depletion of mtDNA on prostate tumorigenesis in vitro and in mouse xenograft model. The proposed development of mtDNA depletion in prostate cells has the significant potential to enhance our understanding of prostate tumorigenesis in the African American population. This proposal addresses the two key objectives of the PAR-09-160 requesting exploratory grants in basic cancer research in cancer health disparities (R21). These objectives include: 1) the development of "new cell culture models/systems designed to investigate cancer disparities" and 2) explores the susceptibility to prostate cancer in African-American men due to "genetic differences" in mtDNA content.