Inhibition of androgen receptor transactivation function by adenovirus type 12 E1A undermines prostate cancer cell survival

Dawei Li, Guimei Tian, Jia Wang, Lisa Y. Zhao, Olivia Co, Zoe C. Underill, Joe S. Mymryk, Frank Claessens, Scott M. Dehm, Yehia Daaka, Daiqing Liao

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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. 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. 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. 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.

Original languageEnglish (US)
Pages (from-to)1140-1156
Number of pages17
JournalProstate
Volume78
Issue number15
DOIs
StatePublished - Nov 1 2018

Bibliographical note

Funding Information:
Science Foundation of China (Grant No. 81502213, to D. Li), KU Leuven grant GOA/15/017 (to FC), and the National Cancer Institute (CA092236, to D. Liao). This work was also supported by the Focused Research and Development Program of Shandong Province (grant No: 2016GSF201171, to D. Li). Dawei Li and Jia Wang were supported by a scholarship from China Scholarship Council (CSC).

Funding Information:
Florida Breast Cancer Foundation; Bankhead-Coley Cancer Research Program, Grant numbers: 09BB-11, 09BW-05, 4BF02, 6BC03; KU Leuven, Grant number: GOA/15/ 017; The National Natural Science Foundation of China, Grant number: 81502213; James and Esther King Biomedical Research Program, Grant number: 6JK03; National Cancer Institute, Grant number: CA092236; Focused Research and Development Program, Grant number: 2016GSF201171

Funding Information:
We thank Arnold Berk, Hancheng Guan, Jianrong Lu, and David Ornelles for providing reagents. The work was supported by grants from Bankhead-Coley Cancer Research Program, and James and Esther King Biomedical Research Program, Florida Department of Health (09BB-11, 09BW-05, 4BF02, 6BC03, and 6JK03 to D. Liao), the Florida Breast Cancer Foundation (to D. Liao), the National Natural

Keywords

  • AR splice variants (AR-Vs)
  • PI3K-kinase (PI3K)-Akt-mTOR signaling
  • androgen receptor
  • prostate cancer gene therapy
  • transcriptional regulation

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