Prostate cancer (PCa) is the second leading cause of cancer-related deaths in American men. Current treatment modalities for metastatic disease and androgen refractory prostate cancer are mostly palliative with poor prognosis. Early diagnosis and prevention are critical to limit the impact of this disease. Epidemiogical studies indicated that patients receiving diabetic drug metformin have lower prostate cancer risk and better prognosis and suggested that the metformin may have anti-neoplastic effects. This study is to elucidate the mechanism by which metformin impede prostate cancer initiation and progression. MYC oncogene is frequently amplified in prostate cancer and its amplification involves in early prostate epithelia cell transformation and the onset of prostate cancer. MYC amplification not only contributes to early transformation of prostate epithelial cells, but also alters prostate tumor sensitivity to mammalian target of rapamycin (mTOR) inhibitors. Our preliminary data demonstrated that metformin reduces the MYC oncogene levels both in vitro and in vivo. Our central hypothesis is that metformin acts as a chemoprevention agent to restrict the initiation of prostatic intraepithelial neoplasia (PIN) and the growth of cancer associated wit down-regulation of MYC.
Aim 1. To examine the inhibitory effect of metformin on prostate cancer initiation and MYC expression in vivo. The working hypothesis is that the metformin alleviates PIN and works synergistically with mTOR inhibitor in Hi-Myc mice. Male Hi-Myc mice will be treated with metformin, metformin plus rapamycin or vehicle for 12- and 24-weeks and MYC, testosterone (T), dihydrotestosterone (DHT), androgen receptor levels, proliferation, apoptosis indices and microvessel density will be determined. Number of PIN and PCa lesions will be enumerated and correlated to MYC levels.
Aim 2. To define the epigenetic responses to metformin in prostate. The working hypothesis is that the metformin reduces MYC associated with epigenetic alterations. We will explore metformin influences on epigenetic alterations in mouse prostates by isolating RNA from early time-point of detectable reduction of MYC protein levels in prostate glands from metformin treated Hi-Myc mice and human primary prostate epithelial cells using Epigenetic Chromatin Modification Enzymes PCR Array. Quantitative RT-PCR and western blots will be used to validate the epigenetic enzymes regulated by metformin. Prostate tissue microarray slides including normal, PIN and PCa tissues will be applied do determine the correlation among these epigenetic enzyme expression levels to PCa progression. This proposed study is the first preclinical study to evaluate metformin as a chemopreventive agent in treating prostate neoplasia and cancer at early stage (i.e. those with PIN or high-grade PIN). The novel combined cancer prevention therapy using metformin and mTOR inhibitors proposed in this study may display promising synergistic efficacy and will be translational to clinical application.

Public Health Relevance

Prostate cancer is the second most common cause of cancer-related deaths in American men. The proposed study will evaluate metformin as chemopreventive agent in a preclinical prostate cancer model and advance our understanding in the anti-neoplasia mechanisms of metformin.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
5R03CA172894-02
Application #
8692692
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Perloff, Marjorie
Project Start
2013-07-01
Project End
2015-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
New York University
Department
Other Basic Sciences
Type
Schools of Dentistry/Oral Hygn
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10012
Guo, Yuqi; Xie, Chengzhi; Li, Xiyan et al. (2017) Succinate and its G-protein-coupled receptor stimulates osteoclastogenesis. Nat Commun 8:15621
Yang, J; Lu, C; Wei, J et al. (2017) Inhibition of KPNA4 attenuates prostate cancer metastasis. Oncogene 36:2868-2878
Yu, T; Wang, C; Yang, J et al. (2017) Metformin inhibits SUV39H1-mediated migration of prostate cancer cells. Oncogenesis 6:e324
Daniels, Garrett; Zhang, Xinmin; Zhong, Xuelin et al. (2016) Cytoplasmic, full length and novel cleaved variant, TBLR1 reduces apoptosis in prostate cancer under androgen deprivation. Oncotarget 7:39556-39571
Yang, J; Wei, J; Wu, Y et al. (2015) Metformin induces ER stress-dependent apoptosis through miR-708-5p/NNAT pathway in prostate cancer. Oncogenesis 4:e158
Guo, Yuqi; Yu, Tao; Yang, Jian et al. (2015) Metformin inhibits salivary adenocarcinoma growth through cell cycle arrest and apoptosis. Am J Cancer Res 5:3600-11
Li, Xiyan; Guo, Yuqi; Yan, Wenbo et al. (2015) Metformin Improves Diabetic Bone Health by Re-Balancing Catabolism and Nitrogen Disposal. PLoS One 10:e0146152
Liang, Jiaqian; Li, Xin; Li, Yirong et al. (2015) LEF1 targeting EMT in prostate cancer invasion is mediated by miR-181a. Am J Cancer Res 5:1124-32
Liang, Jiaqian; Li, Yirong; Daniels, Garrett et al. (2015) LEF1 Targeting EMT in Prostate Cancer Invasion Is Regulated by miR-34a. Mol Cancer Res 13:681-8
Xiao, Shu; Caglar, Elif; Maldonado, Priscilla et al. (2014) Induced expression of nucleolin phosphorylation-deficient mutant confers dominant-negative effect on cell proliferation. PLoS One 9:e109858

Showing the most recent 10 out of 13 publications