Mitochondrial DNA in Mutations in Prostate Cancer

前列腺癌突变中的线粒体 DNA

• 批准号: 7116322
• 负责人: John A. Petros
• 金额: $ 24.14万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7116322
• 关键词: apoptosis; athymic mouse; carcinogenesis; cell cycle; cell line; cell proliferation; clinical research; cytoplasm; flow cytometry; free radical oxygen; gene mutation; human tissue; hybrid cells; mitochondrial DNA; neoplastic growth; nucleic acid sequence; phenotype; prostate neoplasms; transfection; tumor promoters

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：线粒体DNA（mtDNA）突变在多种人类肿瘤中频繁发生，但此类突变的功能后果尚不清楚。我们提案的总体目标是了解 mtDNA 突变如何影响癌细胞的恶性潜力。我们假设 mtDNA 突变增强了肿瘤细胞的存活和增殖，同时减少了恰好获得它们的肿瘤细胞的凋亡。我们进一步提出，mtDNA 突变增加了线粒体活性氧 (ROS) 的产生，并且这种增加的 ROS 产生具有促有丝分裂、增强增殖和减少细胞凋亡的作用。我们实验室的初步数据表明，这种 mtDNA 突变确实能够促进人类前列腺癌异种移植物的生长。为了检验这一假设，提出了 3 个具体目标。首先，我们将生成检验假设所需的实验室结构。具体来说，我们将创建细胞质杂交体（cybrids），将充分表征的前列腺癌细胞系的细胞核与含有突变型或野生型 mtDNA 的细胞质（以及线粒体）结合起来。其次，我们将确定特定突变是否影响恶性表型，测量细胞增殖、凋亡、细胞周期进展和肿瘤发生。最后，我们将确定 ROS 在观察到的表型改变中的作用，确定 ROS 是否是 mtDNA 突变和增强肿瘤生长之间的功能中间体。这些目标的实现将使我们能够确定 mtDNA 突变是否会增强恶性表型，以及这种改变是否是由于 ROS 增加所致。此外，我们将生成细胞、肿瘤和动物模型，以便其他研究人员未来研究 mtDNA 在癌症中的作用，并帮助临床前筛选针对含有 mtDNA 突变的肿瘤的潜在抗肿瘤药物。

项目成果

An inherited heteroplasmic mutation in mitochondrial gene COI in a patient with prostate cancer alters reactive oxygen, reactive nitrogen and proliferation.

• DOI: 10.1155/2013/239257
• 发表时间: 2013
• 期刊: BioMed research international
• 作者: Arnold RS;Sun Q;Sun CQ;Richards JC;O'Hearn S;Osunkoya AO;Wallace DC;Petros JA
• 通讯作者: Petros JA

Mitochondrial DNA mutations in prostate cancer bone metastases.

前列腺癌骨转移中的线粒体 DNA 突变。

• 发表时间: 2015
• 期刊: Journal of nature and science
• 作者: Keith,ChristopherG;Arnold,RebeccaS;Petros,JohnA
• 通讯作者: Petros,JohnA

Mitochondrial NADH-dehydrogenase polymorphisms as sporadic breast cancer risk factor

• DOI: 10.3892/or_00000666
• 发表时间: 2010-02-01
• 期刊: ONCOLOGY REPORTS
• 影响因子: 4.2
• 作者: Czarnecka, Anna M.;Klemba, Aleksandra;Petros, John A.
• 通讯作者: Petros, John A.

Epigenetic modulation of the retinoid X receptor alpha by green tea in the azoxymethane-Apc Min/+ mouse model of intestinal cancer.

• DOI: 10.1002/mc.20542
• 发表时间: 2009-10
• 期刊: Molecular carcinogenesis
• 影响因子: 4.6
• 作者: Volate SR;Muga SJ;Issa AY;Nitcheva D;Smith T;Wargovich MJ
• 通讯作者: Wargovich MJ