Mitochondria! DNA mutations are found in essentially all adult solid tumors yet there remains a great need :or functional and mechanistic studies of these mutations and how they affect the malignant phenotype. Our jroad overarching goal is to understand these mechanisms in order to design more effective therapeutic and diagnostic tools for patient use. Because of our significant patient resources and our substantial previous experience and proven track record in these investigations, we are uniquely positioned to perform rigorous studies of mtDNA mutations in prostate cancer. We present preliminary data that mtDNA mutations enhance cellular reactive oxygen and prostate tumor growth, especially in the bone stromal microenvironment, an observation with obvious relevance to prostate cancer bone metastases. Further, we have begun to identify the (validated) gene expression signature of the interaction between mtDNA mutations in prostate cancer epithelial cells and bone stromal cells, thereby identifying specific signaling pathways (notably FGF-1 and FAK) responsible for this effect. Because these mutations are so common in prostate cancer and appear to be enhancing prostate tumor growth and metastasis, we will test the overall hypothesis that mtDNA mutations in prostate cancer are functionally important in prostate tumorigenesis and metastatic growth and survival in bone. In order to test this hypothesis, three specific aims are proposed. In the first aim we will use new mutations and new prostate cancer nuclear backgrounds to determine the effect of mutations in different respiratory complexes and whether the same signaling pathways already discovered are activated. The effect of mtDNA mutations on reactive oxygen (ROS) production, tumor growth and gene expression will be studied. In the second aim, we will manipulate ROS in both in vivo and in vitro experiments to determine whether this (ROS) is the key signaling pathway for the induction of FGF-1 and focal adhesion kinase (FAK) observed when prostate cancer cells with mtDNA mutation interact with bone stromal cells.
The third aim i s designed to determine whether clinical metastasis involves increased mtDNA mutation and how this affects adaptation in the bone metastatic site and cell signaling.

Public Health Relevance

Mutations in mitochondria! DNA are common in prostate cancer and enhance the cancer's ability to grow, especially in the bone. Because there are so few effective treatments for bone metastases, we will study the ways that these mutations allow this fatal form of prostate cancer to grow. By understanding how this works it is hoped that new treatments may one day be designed targeting this highly malignant form of the disease.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Cedars-Sinai Medical Center
Los Angeles
United States
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Li, Xiangyan; Chen, Yi-Ting; Hu, Peizhen et al. (2014) Fatostatin displays high antitumor activity in prostate cancer by blocking SREBP-regulated metabolic pathways and androgen receptor signaling. Mol Cancer Ther 13:855-66
Miles, Fayth L; Sikes, Robert A (2014) Insidious changes in stromal matrix fuel cancer progression. Mol Cancer Res 12:297-312
Warren, Curtis R; Grindel, Brian J; Francis, Lewis et al. (2014) Transcriptional activation by NF?B increases perlecan/HSPG2 expression in the desmoplastic prostate tumor microenvironment. J Cell Biochem 115:1322-33
Shao, Chen; Liao, Chun-Peng; Hu, Peizhen et al. (2014) Detection of live circulating tumor cells by a class of near-infrared heptamethine carbocyanine dyes in patients with localized and metastatic prostate cancer. PLoS One 9:e88967
Pradhan-Bhatt, Swati; Harrington, Daniel A; Duncan, Randall L et al. (2014) A novel in vivo model for evaluating functional restoration of a tissue-engineered salivary gland. Laryngoscope 124:456-61
Shi, Changhong; Wu, Jason Boyang; Chu, Gina C-Y et al. (2014) Heptamethine carbocyanine dye-mediated near-infrared imaging of canine and human cancers through the HIF-1?/OATPs signaling axis. Oncotarget 5:10114-26
Tighiouart, Mourad; Piantadosi, Steven; Rogatko, André (2014) Dose finding with drug combinations in cancer phase I clinical trials using conditional escalation with overdose control. Stat Med 33:3815-29
Fong, Eliza L S; Martinez, Mariane; Yang, Jun et al. (2014) Hydrogel-based 3D model of patient-derived prostate xenograft tumors suitable for drug screening. Mol Pharm 11:2040-50
Tighiouart, Mourad; Liu, Yuan; Rogatko, André (2014) Escalation with overdose control using time to toxicity for cancer phase I clinical trials. PLoS One 9:e93070
Josson, Sajni; Gururajan, Murali; Hu, Peizhen et al. (2014) miR-409-3p/-5p promotes tumorigenesis, epithelial-to-mesenchymal transition, and bone metastasis of human prostate cancer. Clin Cancer Res 20:4636-46

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