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 1 a, 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.

Public Health Relevance

Our results indicate that reduction of mitochondrial DNA content regulate prostate cancer progression. Confirmation of our hypothesis and an understanding of the underlying mechanisms will lead to development of high impact strategies for new diagnosis, novel approaches to targeted prevention and/or therapy for prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA100846-09
Application #
8256624
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Woodhouse, Elizabeth
Project Start
2003-04-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
9
Fiscal Year
2012
Total Cost
$232,800
Indirect Cost
$72,249
Name
University of Arkansas for Medical Sciences
Department
Biochemistry
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Prior, Sara; Kim, Ara; Yoshihara, Toshitada et al. (2014) Mitochondrial respiratory function induces endogenous hypoxia. PLoS One 9:e88911
Cook, C C; Kim, A; Terao, S et al. (2012) Consumption of oxygen: a mitochondrial-generated progression signal of advanced cancer. Cell Death Dis 3:e258
Zhang, Haihong; Xie, Chenghui; Spencer, Horace J et al. (2011) Obesity and hepatosteatosis in mice with enhanced oxidative DNA damage processing in mitochondria. Am J Pathol 178:1715-27
Suzuki, Seigo; Naito, Akihiro; Asano, Takayuki et al. (2008) Constitutive activation of AKT pathway inhibits TNF-induced apoptosis in mitochondrial DNA-deficient human myelogenous leukemia ML-1a. Cancer Lett 268:31-7
Naito, Akihiro; Cook, Cody C; Mizumachi, Takatsugu et al. (2008) Progressive tumor features accompany epithelial-mesenchymal transition induced in mitochondrial DNA-depleted cells. Cancer Sci 99:1584-8
Mizumachi, Takatsugu; Muskhelishvili, Levan; Naito, Akihiro et al. (2008) Increased distributional variance of mitochondrial DNA content associated with prostate cancer cells as compared with normal prostate cells. Prostate 68:408-17
Mizumachi, T; Suzuki, S; Naito, A et al. (2008) Increased mitochondrial DNA induces acquired docetaxel resistance in head and neck cancer cells. Oncogene 27:831-8
Naito, Akihiro; Carcel-Trullols, Jaime; Xie, Cheng-hui et al. (2008) Induction of acquired resistance to antiestrogen by reversible mitochondrial DNA depletion in breast cancer cell line. Int J Cancer 122:1506-11
Higuchi, Masahiro (2007) Regulation of mitochondrial DNA content and cancer. Mitochondrion 7:53-7
Xie, Cheng-hui; Naito, Akihiro; Mizumachi, Takatsugu et al. (2007) Mitochondrial regulation of cancer associated nuclear DNA methylation. Biochem Biophys Res Commun 364:656-61

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