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Prostate tumor progression by mitochondrial DNA change

线粒体 DNA 变化导致前列腺肿瘤进展

基本信息

批准号：
8461704
负责人：
TIMOTHY C. CHAMBERS
金额：
$ 21.88万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-30 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8461704
关键词：
1-Phosphatidylinositol 3-Kinase 8-Oxoguanine DNA Glycosylase Abbreviations Ablation Accounting Androgen Antagonists Androgen Receptor Androgens Applications Grants Automobile Driving Base Excision Repairs CDH1 gene Cancer Etiology Cancer Patient Castration Cells Cessation of life Charcoal Cholesterol Chronic progressive external ophthalmoplegia CpG Islands DNA DNA-Directed DNA Polymerase Data Development Diagnosis Disease Down-Regulation E-Cadherin Endothelin B Receptor Event GTPase-Activating Proteins Gleason Grade for Prostate Cancer Goals Grant Growth Guanine Nucleotide Exchange Factors Homidium Bromide Hormones Human Hypermethylation In Vitro Investigation LNCaP Lead Link Lovastatin MAPK8 gene MGMT gene Malignant Neoplasms Malignant neoplasm of prostate Mitochondria Mitochondrial DNA Mitogen-Activated Protein Kinases Molecular Morbidity - disease rate Mus NF-kappa B Neoplasm Metastasis Nuclear O(6)-Methylguanine-DNA Methyltransferase OGG1 gene PC3 cell line Pathway interactions Phase Phenotype Phosphatidylinositols Ploidies Population Prevention Process Progress Reports Prostate Prostate Cancer therapy Prostate-Specific Antigen Prostatic Neoplasms Proto-Oncogene Proteins c-akt Reactive Oxygen Species Reagent Recurrence Refractory Reporting Research Resistance Respiratory Chain Role Serum Somatotropin Specimen Staining method Stains Tissue Sample Tissues Transferase Transforming Growth Factor beta Tumor Suppressor Genes United States Up-Regulation Variant Work Xenograft Model Xenograft procedure androgen independent prostate cancer cancer cell epithelial to mesenchymal transition hormone therapy hydroethidine in vivo men mevalonate mortality novel novel strategies overexpression prevent prostate cancer cell public health relevance response stressor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): 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 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. However, the basic mechanism that determines the progression of prostate cancer is lacking. Recently several reports suggest that the change in mtDNA is associated with cancer progression, however, mechanisms has not been established yet. The overall goal of our research is to regulate or protect progression of prostate cancer by demonstrating and understanding the roles of mitochondrial DNA (mtDNA) on prostate cancer progression. During the previous grant period, we used several prostate cancer cell lines, mtDNA deficient cells, cybrids with nuclear DNA from mtDNA-deficient cells with normal mtDNA and tissue samples from prostate cancer specimens and demonstrated the critical roles of mtDNA content on prostate cancer progression. We also showed that Ras pathway is a key sequence for prostate cancer progression starting from reduction of mtDNA content. We also found the link from mtDNA reduction to ras activation. In specific aim 1a, we will investigate the link between reduction of mtDNA to Ras activation. In specific aim 2, we will further investigate the mechanistic link between reduction of mtDNA content to Ras activation followed by hormone refractory changes. In specific aim 3, we will investigate the connection of mtDNA to Ras activation for hormone refractory changes using in vivo mouse xenograft model. In this application, we will further investigate the roles of Ras pathway. An understanding of the mechanisms contributing to the development of androgen-independent and progressed phenotype in prostate cancer is currently lacking. This critical step accounts for the majority of the morbidity and mortality of this disease. Our novel hypothesis and preliminary/progressed report implicates mtDNA in the development of androgen-independence and prostate cancer progression. A confirmation of our hypothesis and an understanding of the underlying mechanisms could lead to novel approaches for prevention or therapy of prostate cancer.

描述（由申请人提供）：前列腺癌是男性中最常见的癌症形式，也是美国男性癌症死亡的第二大原因。前列腺癌的生长最初依赖于雄激素。雄激素消融是前列腺癌的主要治疗方法，可导致雄激素依赖性癌症的消退。然而，许多男性最终死于复发性雄激素不依赖型前列腺癌，这是一种不可避免地进展和转移的致命形式。然而，决定前列腺癌进展的基本机制尚不清楚。最近的一些报道表明，mtDNA的变化与癌症进展有关，然而，其机制尚未确定。我们研究的总体目标是通过证明和理解线粒体DNA （mtDNA）在前列腺癌进展中的作用来调节或保护前列腺癌的进展。在之前的资助期间，我们使用了几种前列腺癌细胞系、mtDNA缺陷细胞、来自mtDNA缺陷细胞的核DNA与正常mtDNA的杂交细胞和来自前列腺癌标本的组织样本，并证明了mtDNA含量在前列腺癌进展中的关键作用。我们还发现Ras通路是从mtDNA含量减少开始的前列腺癌进展的关键序列。我们还发现了mtDNA还原与ras激活之间的联系。在特定的目的1a中，我们将研究mtDNA的减少与Ras激活之间的联系。在具体的目标2中，我们将进一步研究mtDNA含量的降低与Ras激活之间的机制联系，随后是激素的难治性变化。在具体的目标3中，我们将使用小鼠体内异种移植模型研究mtDNA与Ras激活之间的联系，以促进激素的难治性变化。在本应用中，我们将进一步研究Ras通路的作用。目前还缺乏对前列腺癌雄激素非依赖性和进展性表型发展的机制的理解。这一关键步骤是造成这种疾病发病率和死亡率的主要原因。我们的新假设和初步/进展报告暗示mtDNA在雄激素依赖性和前列腺癌进展的发展中起作用。如果我们的假设得到证实，对其潜在机制的理解，可能会导致前列腺癌预防或治疗的新方法。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The awakening of an advanced malignant cancer: an insult to the mitochondrial genome.

DOI：
10.1016/j.bbagen.2011.08.017
发表时间：
2012-05
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
影响因子：
3
作者：
Cook, Cody C.;Higuchi, Masahiro
通讯作者：
Higuchi, Masahiro

Constitutive activation of AKT pathway inhibits TNF-induced apoptosis in mitochondrial DNA-deficient human myelogenous leukemia ML-1a.

DOI：
10.1016/j.canlet.2008.03.020
发表时间：
2008-09
期刊：
Cancer letters
影响因子：
9.7
作者：
Seigo Suzuki;A. Naito;Takayuki Asano;T. Evans;S. Reddy;M. Higuchi
通讯作者：
Seigo Suzuki;A. Naito;Takayuki Asano;T. Evans;S. Reddy;M. Higuchi

Intracellular Oxygen Concentration Determined By Mitochondrial Respiration Regulates Production of Reactive Oxygen Species.

DOI：
发表时间：
2017
期刊：
Integrative cancer biology & research
影响因子：
0
作者：
Ara Kim Wiese;Sara E. Prior;T. Chambers;M. Higuchi
通讯作者：
Ara Kim Wiese;Sara E. Prior;T. Chambers;M. Higuchi

Mitochondrial regulation of cancer associated nuclear DNA methylation.

DOI：
10.1016/j.bbrc.2007.10.047
发表时间：
2007-12
期刊：
Biochemical and biophysical research communications
影响因子：
3.1
作者：
Cheng-hui Xie;A. Naito;T. Mizumachi;T. Evans;M. Douglas;C. Cooney;C. Fan;M. Higuchi
通讯作者：
Cheng-hui Xie;A. Naito;T. Mizumachi;T. Evans;M. Douglas;C. Cooney;C. Fan;M. Higuchi

Intracellular oxygen determined by respiration regulates localization of Ras and prenylated proteins.

由呼吸决定的细胞内氧调节 Ras 和异戊二烯化蛋白的定位。