The N-terminal domain of the androgen receptor drives its nuclear localization in castration-resistant prostate cancer cells

Dar, Javid A.; Masoodi, Khalid Z.; Eisermann, Kurtis; Isharwal, Sudhir; Ai, Junkui; Pascal, Laura E.; Nelson, Joel B.; Wang, Zhou

doi:10.1016/j.jsbmb.2014.03.004

Cited by 13 publications

(9 citation statements)

References 47 publications

(55 reference statements)

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“…The expression vector pEGFP-C1 (Clontech, Mountain View, CA) was used to generate fusion protein constructs with GFP at the N terminus of AR and the NAR mutant for convenient visualization using fluorescent microscopy as described earlier (21). PSA promoter-driven luciferase reporter vector (pPSA6.1) was kindly provided by Dr. Marianne Sadar and a tk promoter-driven Renilla luciferase reporter (pRL-TK) was purchased from Promega (Madison, WI).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Androgen Receptor Nuclear Localization and Castration-Resistant Prostate Tumor Growth by Pyrroloimidazole-based Small Molecules

Masoodi

Dar

et al. 2017

Molecular Cancer Therapeutics

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The androgen receptor (AR) is a ligand-dependent transcription factor that controls the expression of androgen-responsive genes. A key step in androgen action, which is amplified in castration resistant prostate cancer (CRPC), is AR nuclear translocation. Small molecules capable of inhibiting AR nuclear localization could be developed as novel therapeutics for CRPC. We developed a high throughput screen and identified two structurally-related pyrroloimidazoles that could block AR nuclear localization in CRPC cells. We show that these two small molecules, 3-(4-ethoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (EPPI) and 3-(4-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (CPPI) can inhibit the nuclear localization and transcriptional activity of AR and reduce the proliferation of AR-positive but not AR-negative prostate cancer cell lines. EPPI and CPPI did not inhibit nuclear localization of the glucocorticoid receptor or the estrogen receptor, suggesting they selectively target AR. In LNCaP tumor xenografts, CPPI inhibited the proliferation of relapsed LNCaP tumors. These findings suggest that EPPI and CPPI could serve as lead structures for the development of therapeutic agents for CRPC.

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Section: Methodsmentioning

confidence: 99%

Inhibition of Androgen Receptor Nuclear Localization and Castration-Resistant Prostate Tumor Growth by Pyrroloimidazole-based Small Molecules

Masoodi

Dar

et al. 2017

Molecular Cancer Therapeutics

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“…These observations suggested that Hsp70 binds to AR through NTD AR , with the a.a. 294–556 being the most important region for the binding. We have previously shown that region a.a. 294–556 is required for androgen-independent AR nuclear localization in CRPC cells (35). The binding of Hsp70 to this region of AR may suggest a role for Hsp70 in promoting androgen-independent AR nuclear localization in CRPC cells, however further studies will be required to fully elucidate the significance of Hsp70 binding to the C-terminal portion (a.a. 294–556) of NTD AR .…”

Section: Resultsmentioning

confidence: 99%

“…Human AR and its deletion mutants, amino acid 1–560 (N-terminal domain, NTD), 1–665 (NAR), 558–920 (DNA Binding domain, Hinge region and ligand-binding domain, DBDH-LBD), 668–920 (ligand-binding domain, LBD) coding sequence, were inserted separately into pEGFP-C1 vector, generating GFP-AR, GFP-NTD AR , GFP-NAR, GFP-DBDH-LBD AR , and GFP-LBD AR , GFP-AR a.a.1−293 and GFP-AR a.a.294−556 plasmids (35). Hsc70, Hsp70 and its Nucleotide Binding domain (NBD a.a. 1–386), and Substrate Binding domain (SBD a.a. 386–641) coding sequence were inserted into pCMV-3Tag-1A vector to make Flag-Hsc70, Flag-Hsp70, Flag-NBD and Flag-SBD plasmids.…”

Section: Methodsmentioning

confidence: 99%

Hsp70 Binds to the Androgen Receptor N-terminal Domain and Modulates the Receptor Function in Prostate Cancer Cells

Dong

Wang

et al. 2019

Molecular Cancer Therapeutics

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The androgen receptor (AR) is a key driver and therapeutic target in androgen-sensitive prostate cancer, castration resistant prostate cancer (CRPC), and CRPC resistant to abiraterone and enzalutamide, two second generation inhibitors of AR signaling. Since current AR inhibitors target a functioning C-terminal ligand binding domain (LBD), the identification and characterization of co-factors interacting with the N-terminal domain (NTD) of AR may lead to new approaches to target AR signaling in CRPC. Using a pulldown approach coupled with proteomics, we have identified Hsp70 as a co-factor for the NTD of AR in prostate cancer cells. Hsp70 inhibition using siRNA or small molecules indicated that Hsp70 played an important role in the expression and transactivation of endogenous AR. Prostate specific antigen (PSA) promoter/enhancer-driven luciferase assays showed that Hsp70 was also required for transactivation of AR mutant lacking LBD. Furthermore, clonogenic assays showed that an Hsp70 inhibitor, either alone or in synergy with enzalutamide, can inhibit the proliferation of 22Rv1, a widely-used enzalutamide-resistant CRPC prostate cancer cell line. These findings suggest that Hsp70 is a potential therapeutic target for the treatment of enzalutamide-resistant CRPC.

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“… 30 It has also been suggested that expression of the NTD may drive androgen independent nuclear localization and suppress nuclear export of the AR in CRPC. 31 …”

Section: The Role Of the Ar-ntd In Receptor Functionmentioning

confidence: 99%

A sting in the tail: the N-terminal domain of the androgen receptor as a drug target

Monaghan

McEwan

2016

Asian J Androl

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The role of androgen receptor (AR) in the initiation and progression of prostate cancer (PCa) is well established. Competitive inhibition of the AR ligand-binding domain (LBD) has been the staple of antiandrogen therapies employed to combat the disease in recent years. However, their efficacy has often been limited by the emergence of resistance, mediated through point mutations, and receptor truncations. As a result, the prognosis for patients with malignant castrate resistant disease remains poor. The amino-terminal domain (NTD) of the AR has been shown to be critical for AR function. Its modular activation function (AF-1) is important for both gene regulation and participation in protein-protein interactions. However, due to the intrinsically disordered structure of the domain, its potential as a candidate for therapeutic intervention has been dismissed in the past. The recent emergence of the small molecule EPI-001 has provided evidence that AR-NTD can be targeted therapeutically, independent of the LBD. Targeting of AR-NTD has the potential to disrupt multiple intermolecular interactions between AR and its coregulatory binding partners, in addition to intramolecular cross-talk between the domains of the AR. Therapeutics targeting these protein-protein interactions or NTD directly should also have efficacy against emerging AR splice variants which may play a role in PCa progression. This review will discuss the role of intrinsic disorder in AR function and illustrate how emerging therapies might target NTD in PCa.

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The N-terminal domain of the androgen receptor drives its nuclear localization in castration-resistant prostate cancer cells

Cited by 13 publications

References 47 publications

Inhibition of Androgen Receptor Nuclear Localization and Castration-Resistant Prostate Tumor Growth by Pyrroloimidazole-based Small Molecules

Inhibition of Androgen Receptor Nuclear Localization and Castration-Resistant Prostate Tumor Growth by Pyrroloimidazole-based Small Molecules

Hsp70 Binds to the Androgen Receptor N-terminal Domain and Modulates the Receptor Function in Prostate Cancer Cells

A sting in the tail: the N-terminal domain of the androgen receptor as a drug target

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