: Prostate Cancer (PCa) is the second leading cause of cancer-related deaths (after lung cancer) in American men, and the morbidity and the mortality to PCa are even higher in African American men as compared Caucasians. Molecular mechanisms leading to the initiation and progression of PCa including castration resistant prostate cancer (CRPC) or androgen insensitive prostate cancer (AI-PC) are poorly understood. PTEN and p53 are the two most frequently deleted and/ or mutated genes in a variety of human cancers including advanced PCa. Loss of PTEN leads to the hyperactivation of phosphatidylinositol-3-OH kinase (PI3K) and serine/Thr kinase (Akt/PKB). Pten-deficient mice develop high grade prostatic intraepithelial neoplasia (HGPIN) and invasive adenocarcinoma. We have recently demonstrated in our mouse model that the acute inactivation of Pten unexpectedly elicits cellular senescence, a novel mechanism suppressing cancer progression. Aberrant regulation of oncogenes and tumor suppressors including p19Arf, p53 and p21 proteins have been observed in prostate tumors of Pten-deficient mice. We hypothesize that aberrant activation of p19Arf-p53 pathways cooperates with Pten loss to result in prostate cancer progression. We propose to test this hypothesis and to study the molecular mechanisms of regulating Pten-p19Arf-p53 network in prostate cancer using mouse models and cell lines with following Specific Aims: 1) To define the role of p19Arf in prostate cancer progression. 2) To determine the functional roles of p19Arf in the crosstalk of Pten and p53 during tumorigenesis. 3) To address the consequence and relevance of p19Arf inactivation in CRPC growth using Pten/p53 mouse model. Results obtained from this award will provide us valuable insights into novel roles of ARF in prostate cancer progression.

Public Health Relevance

The goal of this project is to elucidate Pten-loss dysregulated pathways in prostate cancer (PCa) by defining novel roles of p19Arf in prostate cancer progression including castration resistant prostate cancer (CRPC) growth. Results will provide significant insights into understanding of mechanisms on the incidence and the mortality of PCa, and disparities among ethnic and racial groups.

Agency
National Institute of Health (NIH)
Institute
National Institute on Minority Health and Health Disparities (NIMHD)
Type
Research Project (R01)
Project #
5R01MD004038-02
Application #
7938940
Study Section
Special Emphasis Panel (ZMD1-PA (R4))
Program Officer
Rajapakse, Nishadi
Project Start
2009-09-25
Project End
2014-04-30
Budget Start
2010-05-04
Budget End
2011-04-30
Support Year
2
Fiscal Year
2010
Total Cost
$366,250
Indirect Cost
Name
Meharry Medical College
Department
Biochemistry
Type
Schools of Medicine
DUNS #
041438185
City
Nashville
State
TN
Country
United States
Zip Code
37208
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Xie, Yingqiu; Lu, Wenfu; Liu, Shenji et al. (2016) MMP7 interacts with ARF in nucleus to potentiate tumor microenvironments for prostate cancer progression in vivo. Oncotarget 7:47609-47619
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Lu, Wenfu; Liu, Shenji; Li, Bo et al. (2015) SKP2 inactivation suppresses prostate tumorigenesis by mediating JARID1B ubiquitination. Oncotarget 6:771-88
Chen, Zhenbang; Lu, Wenfu (2015) Roles of ubiquitination and SUMOylation on prostate cancer: mechanisms and clinical implications. Int J Mol Sci 16:4560-80
Wanjala, Jackie; Taylor, Barry S; Chapinski, Caren et al. (2015) Identifying actionable targets through integrative analyses of GEM model and human prostate cancer genomic profiling. Mol Cancer Ther 14:278-88
Xie, Yingqiu; Lu, Wenfu; Liu, Shenji et al. (2014) Crosstalk between nuclear MET and SOX9/?-catenin correlates with castration-resistant prostate cancer. Mol Endocrinol 28:1629-39
Li, Bo; Lu, Wenfu; Chen, Zhenbang (2014) Regulation of Androgen Receptor by E3 Ubiquitin Ligases: for More or Less. Receptors Clin Investig 1:

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