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.
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.
|Li, Qiuhui; Deng, Qu; Chao, Hsueh-Ping et al. (2018) Linking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses. Nat Commun 9:3600|
|Fiandalo, Michael V; Wilton, John H; Mantione, Krystin M et al. (2018) Serum-free complete medium, an alternative medium to mimic androgen deprivation in human prostate cancer cell line models. Prostate 78:213-221|
|Itkonen, Harri M; Brown, Michael; Urbanucci, Alfonso et al. (2017) Lipid degradation promotes prostate cancer cell survival. Oncotarget 8:38264-38275|
|Askew, Emily B; Bai, Suxia; Parris, Amanda B et al. (2017) Androgen receptor regulation by histone methyltransferase Suppressor of variegation 3-9 homolog 2 and Melanoma antigen-A11. Mol Cell Endocrinol 443:42-51|
|Komisarof, Justin; McCall, Matthew; Newman, Laurel et al. (2017) A four gene signature predictive of recurrent prostate cancer. Oncotarget 8:3430-3440|
|Su, Shifeng; Chen, Xiaoyu; Geng, Jiang et al. (2017) Melanoma antigen-A11 regulates substrate-specificity of Skp2-mediated protein degradation. Mol Cell Endocrinol 439:1-9|
|Stocking, John J; Fiandalo, Michael V; Pop, Elena A et al. (2016) Characterization of Prostate Cancer in a Functional Eunuch. J Natl Compr Canc Netw 14:1054-60|
|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|
|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|
|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|
Showing the most recent 10 out of 103 publications