Mini-review: Foldosome regulation of androgen receptor action in prostate cancer

Cano, Laia Querol; Lavery, Derek N.; Bevan, Charlotte L.

doi:10.1016/j.mce.2013.01.023

Cited by 54 publications

(34 citation statements)

References 152 publications

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“…7d). The HSP90 complex plays a major role in stabilizing unliganded AR24. Therefore, we examined whether AIL affected the members of the HSP90 complex.…”

Section: Resultsmentioning

confidence: 99%

“…Foldosome complex assembly occurs through a series of steps, beginning with HSP40 and HSP70 binding to AR, followed by HSP90 and HOP, and then succeeded by ATP-dependent binding of p23, FKBP51 and FKBP52 which displace HSP40, HSP70, and HOP24. Additional foldosome proteins include cdc37 and HDAC6 (36).…”

Section: Resultsmentioning

confidence: 99%

“…We found that AIL disrupted the interaction between AR and the chaperones HSP90, HSP70 and HSP40, and consequently AR was ubiquitinated and degradated through the proteasome-mediated pathway. When not bound to ligand, AR resides in the cytosol bound to the foldosome, a complex of heat shock, chaperone and co-chaperone proteins including HSP90, HSP70, HSP40 and p23, among others24. The HSP90 dimer undergoes an ATP-driven reaction cycle.…”

Section: Discussionmentioning

confidence: 99%

“…24). Intriguingly, some inhibitors of HSP90 such as AT13387 decrease the expression of several HSP90 client proteins including wild-type AR and AR–V7 (an AR splice variant), and also disrupt nuclear localization of the AR.…”

mentioning

confidence: 99%

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Ailanthone targets p23 to overcome MDV3100 resistance in castration-resistant prostate cancer

Peng

Wang

et al. 2016

Nat Commun

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Androgen receptor (AR) antagonist MDV3100 is the first therapeutic approach in treating castration-resistant prostate cancer (CRPC), but tumours frequently become drug resistant via multiple mechanisms including AR amplification and mutation. Here we identify the small molecule Ailanthone (AIL) as a potent inhibitor of both full-length AR (AR-FL) and constitutively active truncated AR splice variants (AR-Vs). AIL binds to the co-chaperone protein p23 and prevents AR's interaction with HSP90, thus resulting in the disruption of the AR-chaperone complex followed by ubiquitin/proteasome-mediated degradation of AR as well as other p23 clients including AKT and Cdk4, and downregulates AR and its target genes in PCa cell lines and orthotopic animal tumours. In addition, AIL blocks tumour growth and metastasis of CRPC. Finally, AIL possesses favourable drug-like properties such as good bioavailability, high solubility, lack of CYP inhibition and low hepatotoxicity. In general, AIL is a potential candidate for the treatment of CRPC.

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“…7d). The HSP90 complex plays a major role in stabilizing unliganded AR24. Therefore, we examined whether AIL affected the members of the HSP90 complex.…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Ailanthone targets p23 to overcome MDV3100 resistance in castration-resistant prostate cancer

Peng

Wang

et al. 2016

Nat Commun

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“…Upon androgen binding, AR undergoes a conformational change leading to AR-HSP90 dissociation, rapid nuclear translocation, and AR target gene transcription [9]. Unchecked, this process eventually leads to prostate tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

Acetylation of androgen receptor by ARD1 promotes dissociation from HSP90 complex and prostate tumorigenesis

et al. 2016

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Prostate cancer is an androgen receptor (AR)-driven disease and post-translational modification of AR is critical for AR activation. We previously reported that Arrest-defective protein 1 (ARD1) is an oncoprotein in prostate cancer. It acetylates and activates AR to promote prostate tumorigenesis. However, the ARD1-targeted residue within AR and the mechanisms of the acetylation event in prostate tumorigenesis remained unknown. In this study, we show that ARD1 acetylates AR at lysine 618 (K618) in vitro and in vivo. An AR construct with the charged lysine substitution by arginine (AR-618R) reduces RNA Pol II binding, AR transcriptional activity, prostate cancer cell growth, and xenograft tumor formation due to attenuation of AR nuclear translocation, whereas, construct mimicking neutral polar substitution acetylation at K618 by glutamine (AR-618Q) enhanced these effects beyond that of the wild-type AR. Mechanistically, ARD1 forms a ternary complex with AR and HSP90 in vitro and in vivo. Expression of ARD1 increases levels of AR acetylation and AR-HSP90 dissociation in a dose dependent manner. Moreover, the AR acetylation defective K618R mutant is unable to dissociate from HSP90 while the HSP90-dissociated AR is acetylated following ligand exposure. This work identifies a new mechanism for ligand-induced AR-HSP90 dissociation and AR activation. Targeting ARD1-mediated AR acetylation may be a potent intervention for AR-dependent prostate cancer therapy.

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Inactivation of ID4 promotes a CRPC phenotype with constitutive AR activation through FKBP52

et al. 2017

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Castration‐resistant prostate cancer (CRPC) is the emergence of prostate cancer cells that have adapted to the androgen‐depleted environment of the prostate. In recent years, targeting multiple chaperones and co‐chaperones (e.g., Hsp27, FKBP52) that promote androgen receptor (AR) signaling and/or novel AR regulatory mechanisms have emerged as promising alternative treatments for CRPC. We have shown that inactivation of inhibitor of differentiation 4 (ID4), a dominant‐negative helix loop helix protein, promotes de novo steroidogenesis and CRPC with a gene expression signature that resembles constitutive AR activity in castrated mice. In this study, we investigated the underlying mechanism through which loss of ID4 potentiates AR signaling. Proteomic analysis between prostate cancer cell line LNCaP (L+ns) and LNCaP lacking ID4 (L(−)ID4) revealed elevated levels of Hsp27 and FKBP52, suggesting a role for these AR‐associated co‐chaperones in promoting constitutively active AR signaling in L(−)ID4 cells. Interestingly, protein interaction studies demonstrated a direct interaction between ID4 and the 52‐kDa FK506‐binding protein (FKBP52) in vitro, but not with AR. An increase in FKBP52‐dependent AR transcriptional activity was observed in L(−)ID4 cells. Moreover, pharmacological inhibition of FKBP52‐AR signaling, by treatment with MJC13, attenuated the tumor growth, weight, and volume in L(−)ID4 xenografts. Together, our results demonstrate that ID4 selectively regulates AR activity through direct interaction with FKBP52, and its loss, promotes CRPC through FKBP52‐mediated AR signaling.

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Mini-review: Foldosome regulation of androgen receptor action in prostate cancer

Cited by 54 publications

References 152 publications

Ailanthone targets p23 to overcome MDV3100 resistance in castration-resistant prostate cancer

Ailanthone targets p23 to overcome MDV3100 resistance in castration-resistant prostate cancer

Acetylation of androgen receptor by ARD1 promotes dissociation from HSP90 complex and prostate tumorigenesis

Inactivation of ID4 promotes a CRPC phenotype with constitutive AR activation through FKBP52

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