Prostate tumor progression by mitochondrial DNA change

描述（由申请人提供）：前列腺癌是男性最常见的癌症形式，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是雄激素依赖性的。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非依赖性前列腺癌，这是一种不可避免地进展和转移的致命形式。然而，缺乏决定前列腺癌进展的基本机制。近年来有报道认为线粒体DNA的改变与肿瘤的进展有关，但其机制尚不明确。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。在上一个资助期间，我们使用了几种前列腺癌细胞系、mtDNA缺陷细胞、mtDNA缺陷细胞的核DNA与正常mtDNA的胞质杂交体以及前列腺癌标本的组织样本，并证明了mtDNA含量对前列腺癌进展的关键作用。我们还表明，Ras途径是从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。在具体目标1a中，我们将研究mtDNA还原与Ras激活之间的联系。在具体目标2中，我们将进一步研究线粒体DNA含量减少与Ras激活以及激素抵抗性变化之间的机制联系。在具体目标3中，我们将使用体内小鼠异种移植模型研究mtDNA与Ras激活对于激素难治性变化的联系。在本申请中，我们将进一步研究Ras途径的作用。目前尚缺乏对前列腺癌雄激素非依赖性和进展性表型发展机制的了解。这一关键步骤占该疾病发病率和死亡率的大部分。我们的新假设和初步/进展报告暗示mtDNA在雄激素非依赖性和前列腺癌进展的发展。我们的假设的证实和对潜在机制的理解可能会导致预防或治疗前列腺癌的新方法。

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.