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

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

doi:10.1172/jci141335

Cited by 33 publications

(29 citation statements)

References 64 publications

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“…Here, only a change in nuclear protein level after antiandrogen treatment could be observed, indicating a possible role of AR protein turnover in the regulation of nuclear AR. This hypothesis is in line with the observations by Lv et al demonstrating that targeting the AR androgens cause MDM2 mediated nuclear AR degradation and not nuclear AR export [ 48 ]. Other studies with Enzalutamide, Apalutamide, and Darolutamide also confirmed reduced nuclear protein than in AR translocation to the cytoplasm [ 13 , 39 , 49 ].…”

Section: Discussionsupporting

confidence: 92%

A Systematic Comparison of Antiandrogens Identifies Androgen Receptor Protein Stability as an Indicator for Treatment Response

Siciliano

Simons

Beier

et al. 2021

Life

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Antiandrogen therapy is a primary treatment for patients with metastasized prostate cancer. Whilst the biologic mechanisms of antiandrogens have been extensively studied, the operating protocols used for the characterization of these drugs were not identical, limiting their comparison. Here, the antiandrogens Bicalutamide, Enzalutamide, Apalutamide, and Darolutamide were systematically compared using identical experimental setups. Androgen-dependent LNCaP and LAPC4 cells as well as androgen-independent C4-2 cells were treated with distinct concentrations of antiandrogens. Androgen receptor (AR)-mediated gene transactivation was determined using qPCR. Cell viability was measured by WST1 assay. Protein stability and AR localization were determined using western blot. Response to the tested antiandrogens across cellular backgrounds differed primarily in AR-mediated gene transactivation and cell viability. Antiandrogen treatment in LNCaP and LAPC4 cells resulted in AR protein level reduction, whereas in C4-2 cells marginal decreased AR protein was observed after treatment. In addition, AR downregulation was already detectable after 4 h, whereas reduced AR-mediated gene transactivation was not observed before 6 h. None of the tested antiandrogens displayed an advantage on the tested parameters within one cell line as opposed to the cellular background, which seems to be the primary influence on antiandrogen efficacy. Moreover, the results revealed a prominent role in AR protein stability. It is one of the first events triggered by antiandrogens and correlated with antiandrogen efficiency. Therefore, AR stability may surrogate antiandrogen response and may be a possible target to reverse antiandrogen resistance.

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Section: Discussionsupporting

confidence: 92%

A Systematic Comparison of Antiandrogens Identifies Androgen Receptor Protein Stability as an Indicator for Treatment Response

Siciliano

Simons

Beier

et al. 2021

Life

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“…As AR activity correlated with NRDP1 nuclear localization in the primary tumors, we focused on determining whether the AR could play a role in nuclear transport of NRDP1. Binding of androgen to the AR promotes the transport of AR into the nucleus [31] and the AR has been shown to facilitate the nuclear transport of other molecules, for example beta-catenin [20,21]. Our data demonstrate that manipulation of AR nuclear expression and/or activation and translocation can impact nuclear NRDP1 levels in androgen sensitive LNCaP and MDA-PCa-2b cells.…”

Section: Transport Of Nrdp1 Into the Nucleus Is Associated With Nuclear Transport Of The Androgen Receptormentioning

confidence: 63%

Androgen Receptor-Mediated Nuclear Transport of NRDP1 in Prostate Cancer Cells Is Associated with Worse Patient Outcomes

Steele

Sam

Evans

et al. 2021

Cancers

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To our knowledge, our group is the first to demonstrate that NRDP1 is located in the nucleus as well as the cytoplasm of CaP cells. Subcellular fractionation, immunohistochemistry, and immunofluorescence analysis combined with confocal microscopy were used to validate this finding. Subcellular fractionation followed by western blot analysis revealed a strong association between AR and NRDP1 localization when AR expression and/or cellular localization was manipulated via treatment with R1881, AR-specific siRNA, or enzalutamide. Transfection of LNCaP with various NRDP1 and AR constructs followed by immunoprecipitation confirmed binding of NRDP1 to AR is possible and determined that binding requires the hinge region of AR. Co-transfection with NRDP1 constructs and HA-ubiquitin followed by subcellular fractionation confirmed that nuclear NRDP1 retains its ubiquitin ligase activity. We also show that increased nuclear NRDP1 is associated with PSA recurrence in CaP patients (n = 162, odds ratio; 1.238, p = 0.007) and that higher levels of nuclear NRDP1 are found in castration resistant cell lines (CWR22Rv1 and PC3) compared to androgen sensitive cell lines (LNCaP and MDA-PCa-3B). The combined data indicate that NRDP1 plays a role in mediating CaP progression and supports further investigation of both the mechanism by which nuclear transport occurs and the identification of specific nuclear targets.

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“…However, stronger inhibition of AR signaling also leads to cancer cell resistance to anti-androgens. In the CRPC stage, AR undergoes changes in expression (Abida et al, 2019), structure (Kumar et al, 2016) and intracellular localization (Lv et al, 2020). These alterations cause AR signaling to re-activate and promote cancer cell proliferation even in the presence of secondary anti-androgens, such as enzalutamide or apalutamide (Fujita & Nonomura, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…The CETSA assay was performed as previously described (Lv et al, 2020). Prostate cancer cells were treated with 50 μM ivermectin for 1 hour.…”

Section: Cellular Thermal Shift Assay (Cetsa)mentioning

confidence: 99%

Integrated analysis reveals FOXA1 and Ku70/Ku80 as direct targets of ivermectin in prostate cancer

Luo

et al. 2022

Preprint

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Ivermectin is a widely used antiparasitic drug and shows promising anticancer activity in various cancer types. Although multiple signaling pathways modulated by ivermectin have been identified, few studies have focused on the exact target of ivermectin. Herein, we report the pharmacological effects and direct targets of ivermectin in prostate cancer (PCa). Ivermectin caused G0/G1 arrest, induced cell apoptosis, DNA damage, and decreased androgen receptor (AR) signaling in PCa cells. Using integrated omics profiling, including RNA-seq and thermal proteome profiling, we found that the forkhead box protein A1 (FOXA1) and non-homologous end joining (NHEJ) repair executer Ku70/Ku80 were the direct targets of ivermectin. The binding of ivermectin and FOXA1 reduced the chromatin accessibility of AR and the G0/G1 cell cycle regulator E2F1, leading to cell proliferation inhibition. The binding of ivermectin and Ku70/Ku80 impaired the NHEJ repair ability. Cooperating with the downregulation of homologous recombination repair after AR inhibition, ivermectin triggered synthetic lethality. Our findings demonstrate the anticancer effect of ivermectin in prostate cancer, indicating that its use may be a new therapeutic approach for PCa.

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

Cited by 33 publications

References 64 publications

A Systematic Comparison of Antiandrogens Identifies Androgen Receptor Protein Stability as an Indicator for Treatment Response

A Systematic Comparison of Antiandrogens Identifies Androgen Receptor Protein Stability as an Indicator for Treatment Response

Androgen Receptor-Mediated Nuclear Transport of NRDP1 in Prostate Cancer Cells Is Associated with Worse Patient Outcomes

Integrated analysis reveals FOXA1 and Ku70/Ku80 as direct targets of ivermectin in prostate cancer

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