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Inhibition of androgen receptor transactivation function by adenovirus type 12 E1A undermines prostate cancer cell survival.
- Source :
-
The Prostate [Prostate] 2018 Nov; Vol. 78 (15), pp. 1140-1156. Date of Electronic Publication: 2018 Jul 15. - Publication Year :
- 2018
-
Abstract
- Background: Mutations or truncation of the ligand-binding domain (LBD) of androgen receptor (AR) underlie treatment resistance for prostate cancer (PCa). Thus, targeting the AR N-terminal domain (NTD) could overcome such resistance.<br />Methods: Luciferase reporter assays after transient transfection of various DNA constructs were used to assess effects of E1A proteins on AR-mediated transcription. Immunofluorescence microscopy and subcellular fractionation were applied to assess intracellular protein localization. Immunoprecipitation and mammalian two-hybrid assays were used to detect protein-protein interactions. qRT-PCR was employed to determine RNA levels. Western blotting was used to detect protein expression in cells. Effects of adenoviruses on prostate cancer cell survival were evaluated with CellTiter-Glo assays.<br />Results: Adenovirus 12 E1A (E1A12) binds specifically to the AR. Interestingly, the full-length E1A12 (266 aa) preferentially binds to full-length AR, while the small E1A12 variant (235 aa) interacts more strongly with AR-V7. E1A12 promotes AR nuclear translocation, likely through mediating intramolecular AR NTD-LBD interactions. In the nucleus, AR and E1A12 co-expression in AR-null PCa cells results in E1A12 redistribution from nuclear foci containing CBX4 (also known as Pc2), suggesting a preferential AR-E1A12 interaction over other E1A12 interactors. E1A12 represses AR-mediated transcription in reporter gene assays and endogenous AR target genes such as ATAD2 and MYC in AR-expressing PCa cells. AR-expressing PCa cells are more sensitive to death induced by a recombinant adenovirus expressing E1A12 (Ad-E1A12) than AR-deficient PCa cells, which could be attributed to the increased viral replication promoted by androgen stimulation. Targeting the AR by E1A12 promotes apoptosis in PCa cells that express the full-length AR or C-terminally truncated AR variants. Importantly, inhibition of mTOR signaling that blocks the expression of anti-apoptotic proteins markedly augments Ad-E1A12-induced apoptosis of AR-expressing cells. Mechanistically, Ad-E1A12 infection triggers apoptotic response while activating the PI3K-AKT-mTOR signaling axis; thus, mTOR inhibition enhances apoptosis in AR-expressing PCa cells infected by Ad-E1A12.<br />Conclusion: Ad12 E1A inhibits AR-mediated transcription and suppresses PCa cell survival, suggesting that targeting the AR by E1A12 might have therapeutic potential for treating advanced PCa with heightened AR signaling.<br /> (© 2018 Wiley Periodicals, Inc.)
- Subjects :
- Adenovirus E1A Proteins genetics
Adenoviruses, Human genetics
Adenoviruses, Human metabolism
Cell Line, Tumor
Cell Survival physiology
HEK293 Cells
Humans
Male
Prostatic Neoplasms genetics
Prostatic Neoplasms metabolism
Prostatic Neoplasms virology
Protein Domains
Transcriptional Activation
Transfection
Adenovirus E1A Proteins metabolism
Prostatic Neoplasms therapy
Receptors, Androgen genetics
Receptors, Androgen metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1097-0045
- Volume :
- 78
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- The Prostate
- Publication Type :
- Academic Journal
- Accession number :
- 30009471
- Full Text :
- https://doi.org/10.1002/pros.23689