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Regulation and targeting of androgen receptor nuclear localization in castration-resistant prostate cancer
Shidong Lv, … , Wenhua Huang, Zhou Wang
Shidong Lv, … , Wenhua Huang, Zhou Wang
Published December 17, 2020
Citation Information: J Clin Invest. 2021;131(4):e141335. https://doi.org/10.1172/JCI141335.
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Research Article Oncology Article has an altmetric score of 4

Regulation and targeting of androgen receptor nuclear localization in castration-resistant prostate cancer

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Abstract

Nuclear localization of the androgen receptor (AR) is necessary for its activation as a transcription factor. Defining the mechanisms regulating AR nuclear localization in androgen-sensitive cells and how these mechanisms are dysregulated in castration-resistant prostate cancer (CRPC) cells is fundamentally important and clinically relevant. According to the classical model of AR intracellular trafficking, androgens induce AR nuclear import and androgen withdrawal causes AR nuclear export. The present study has led to an updated model that AR could be imported in the absence of androgens, ubiquitinated, and degraded in the nucleus. Androgen withdrawal caused nuclear AR degradation, but not export. In comparison with their parental androgen-sensitive LNCaP prostate cancer cells, castration-resistant C4-2 cells exhibited reduced nuclear AR polyubiquitination and increased nuclear AR level. We previously identified 3-(4-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (CPPI) in a high-throughput screen for its inhibition of androgen-independent AR nuclear localization in CRPC cells. The current study shows that CPPI is a competitive AR antagonist capable of enhancing AR interaction with its E3 ligase MDM2 and degradation of AR in the nuclei of CRPC cells. Also, CPPI blocked androgen-independent AR nuclear import. Overall, these findings suggest the feasibility of targeting androgen-independent AR nuclear import and stabilization, two necessary steps leading to AR nuclear localization and activation in CRPC cells, with small molecule inhibitors.

Authors

Shidong Lv, Qiong Song, Guang Chen, Erdong Cheng, Wei Chen, Ryan Cole, Zeyu Wu, Laura E. Pascal, Ke Wang, Peter Wipf, Joel B. Nelson, Qiang Wei, Wenhua Huang, Zhou Wang

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Figure 7

CPPI inhibited LNCaP95 cell proliferation and full-length AR interaction with ARv7.

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CPPI inhibited LNCaP95 cell proliferation and full-length AR interaction...
(A) LNCaP95 cell proliferation following treatment with indicated concentrations of CPPI for 1, 2, and 3 days (n = 3). (B) BrdU incorporation in LNCaP95 cells treated with CPPI. Right panel shows percentages of the LNCaP95 cells stained with BrdU (n = 4). Original magnification, ×40. (C) Cell-cycle analysis of LNCaP95 cells treated with CPPI (n = 3). (D) Western blot of AR, AR S81, PSA, and UBE2C in LNCaP95 cells treated with CPPI. GAPDH was probed as loading control. (E) qPCR analysis of AR target genes (KLK3, TMPRSS2, and NKX3-1) and ARV target genes (UBE2C and CDC20) in LNCaP95 cells treated with CPPI (n = 3). (F) Western blot analysis of AR and ARv7 in the nuclear and cytoplasmic extracts of LNCaP95 cells treated with CPPI. (G) BRET assay of AR-FL and ARv7 interaction following CPPI treatment (n = 3). Quantitative data are presented as mean ± SEM, and all data represent 1 of at least 2 independent experiments with consistent results. Unpaired t test (A) or 1-way ANOVA with Dunnett’s multiple-comparison post test (B, C, E, and G) was used to determine statistical significance. *P < 0.05; **P < 0.01; ***P < 0.001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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