The androgen receptor (AR) is an essential transcription factor in prostate cancer development and progression that mediates its effects through interactions with coregulatory proteins. Melanoma antigen gene protein-11 (IVlAGE-11) Is an AR coregulator and IVIAGE gene member family of cancer-testis antigens expressed in androgen-dependent prostate cancer and overexpressed in castration-recurrent prostate cancer. MAGE-11 interacts with the AR Nl-l2-terminal FXXLF motif to increase AR transcriptional activity. Described in this proposal are studies to identify the mechanisms whereby MAGE-11 contributes to AR reactivation and promotion of recurrent prostate cancer growth. The studies test the hypothesis that MAGE-11 is a product of a proto-oncogene that increases AR transcriptional activity through interactions with the retinoblastoma pocket proteins, Rb and/or p107 (Rb/p107).
Aim 1 in collaboration with Project 1 will establish the requirement for MAGE-11 in AR mediated prostate cancer cell growth using lentiviral vectors to silence and recover MAGE-11 expression. The cell cycle regulation of MAGE-11 and effects of MAGE-11 knockdown on the cell cycle, cell senescence and/or apoptosis will be determined. Lentiviral overexpression of MAGE-11 will be performed to simulate the cellular milieu of recurrent prostate cancer.
Aim 2 pursues preliminary evidence that MAGE-11 sequesters the hypophosphorylated form of Rb/p107 to promote cell cycle progression. The ability of MAGE-11 to interact with Rb/p107 will be assessed with respect to the phosphorylation of MAGE-11 and Rb/p107 and the coregulatory effects of MAGE-11 and Rb/p107 on AR transcriptional activity.
Aim 3 investigates functional effects of AR and MAGE-11 interactions with Skp2 (S phase kinase-associated protein 2) to modulate Skp2 activity and degradation, Rb/p107 effects on the Skp2-p27-Kip1 pathway and the E2F transcription factor-regulated gene network required for the G1/S transition. The studies are based on preliminary evidence that AR and MAGE-11 stabilize Skp2. The overall goal of the proposed experimental plan is to establish the mechanisms by which MAGE-11 contributes to the reactivation of AR to promote the growth and progression of prostate cancer.

Public Health Relevance

Prostate cancer is a multifactorial disease in which the androgen receptor (AR) and its coregulators have a central role. Recent studies identified MAGE-11 as a regulatory protein that links AR to cell cycle progression and prostate cancer cell proliferation. The proposed mechanistic studies may provide a basis for the development of new treatment strategies to arrest castration-recurrent growth of prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA077739-15
Application #
8650263
Study Section
Special Emphasis Panel (ZCA1-RPRB-O)
Project Start
Project End
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
15
Fiscal Year
2014
Total Cost
$249,793
Indirect Cost
$33,756
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Frasinyuk, Mykhaylo S; Mrug, Galyna P; Bondarenko, Svitlana P et al. (2016) Antineoplastic Isoflavonoids Derived from Intermediate ortho-Quinone Methides Generated from Mannich Bases. ChemMedChem 11:600-11
Montecinos, Viviana P; Morales, Claudio H; Fischer, Thomas H et al. (2015) Selective targeting of bioengineered platelets to prostate cancer vasculature: new paradigm for therapeutic modalities. J Cell Mol Med 19:1530-7
Torres-Estay, Verónica; Carreño, Daniela V; San Francisco, Ignacio F et al. (2015) Androgen receptor in human endothelial cells. J Endocrinol 224:R131-7
Payne Ondracek, Rochelle; Cheng, Jinrong; Gangavarapu, Kalyan J et al. (2015) Impact of devascularization and tissue procurement on cell number and RNA integrity in prostatectomy tissue. Prostate 75:1910-5
Minges, John T; Grossman, Gail; Zhang, Ping et al. (2015) Post-translational Down-regulation of Melanoma Antigen-A11 (MAGE-A11) by Human p14-ARF Tumor Suppressor. J Biol Chem 290:25174-87
Koulikov, Dmitry; Mohler, Maura C; Mehedint, Diana C et al. (2014) Low detectable prostate specific antigen after radical prostatectomy--treat or watch? J Urol 192:1390-6
Wilton, John H; Titus, Mark A; Efstathiou, Eleni et al. (2014) Androgenic biomarker prof|ling in human matrices and cell culture samples using high throughput, electrospray tandem mass spectrometry. Prostate 74:722-31
Heemers, Hannelore V; Mohler, James L (2014) Words of wisdom. Re: Activity of cabazitaxel in castration-resistant prostate cancer progressing after docetaxel and next-generation endocrine agents. Eur Urol 66:597
Kim, Won; Zhang, Li; Wilton, John H et al. (2014) Sequential use of the androgen synthesis inhibitors ketoconazole and abiraterone acetate in castration-resistant prostate cancer and the predictive value of circulating androgens. Clin Cancer Res 20:6269-76
Tan, Jiann-an; Bai, Suxia; Grossman, Gail et al. (2014) Mechanism of androgen receptor corepression by CKβBP2/CRIF1, a multifunctional transcription factor coregulator expressed in prostate cancer. Mol Cell Endocrinol 382:302-13

Showing the most recent 10 out of 95 publications