Bruceantin targets HSP90 to overcome resistance to hormone therapy in castration-resistant prostate cancer
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PROVIDER: PRJNA608261 | ENA |
REPOSITORIES: ENA
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Project description:Here we report the identification of bruceantin as a highly potent inhibitor of HSP90. RNA-seq analysis demonstrated bruceantin inhibits the transcriptional activity of androgen receptor and androgen receptor variant 7 and downregulates their target genes in castration-resistant prostate cancer cells.
2021-02-24 | GSE145790 | GEO
Project description:Rationale: Aberrant androgen receptor (AR) signaling via full-length AR (AR-FL) and constitutively active AR variant 7 (AR-V7) plays a key role in the development of castration-resistant prostate cancer (CRPC) and resistance to hormone therapies. Simultaneous targeting of AR-FL and AR-V7 may be a promising strategy to overcome resistance to hormone therapy. This study aimed to identify novel drug candidates co-targeting AR-FL and AR-V7 activities and elucidate their molecular mechanism of anti-CRPC activities. Methods: Using a CRPC cell-based reporter assay system, we screened a small library of antimalarial agents to explore the possibility of repositioning them for CRPC treatment and identified bruceantin (BCT) as a potent anti-CRPC drug candidate. A series of cell-based, molecular, biochemical, and in vivo approaches were performed to evaluate the therapeutic potential and molecular mechanism of BCT in CRPC. These approaches include reporter gene assays, cell proliferation, RNA-seq, qRT-PCR, mouse xenografts, co-immunoprecipitation, GST pull-down, immobilized BCT pull-down, molecular modeling, and bioinformatic analyses. Results: We identified BCT as a highly potent inhibitor co-targeting AR-FL and AR-V7 activity. BCT inhibits the transcriptional activity of AR-FL/AR-V7 and downregulates their target genes in CRPC cells. In addition, BCT efficiently suppresses tumor growth and metastasis of CRPC cells. Mechanistically, BCT disrupts the interaction of HSP90 with AR-FL/AR-V7 by directly binding to HSP90 and inhibits HSP90 chaperone function, leading to degradation of AR-FL/AR-V7 through the ubiquitin-proteasome system. Clinically, HSP90 expression is upregulated and correlated with AR/AR-V7 levels in CRPC. Conclusion: Our findings suggest that BCT could serve as a promising therapeutic candidate against CRPC and highlight the potential benefit of targeting AR-FL/AR-V7-HSP90 axis to overcome resistance caused by aberrant AR-FL/AR-V7 signaling.
| S-EPMC7738850 | biostudies-literature
Project description:Anti-androgen therapies including the new androgen receptor (AR) antagonist MDV3100 are the first therapeutic approach in treating prostate cancer (PCa). However, tumors frequently become castration resistant through multiple mechanisms including alternative expression of AR splice variants. To identify new inhibitors which block both full-length AR (AR-FL) and constitutively-active truncated AR splice variants (AR-Vs), a library of natural compounds was screened for molecules that could inhibit AR-driven transcription in PCa cells expressing AR-FL or AR-Vs. We identified the small-molecule Ailanthone (AIL) as a potent inhibitor of both AR-FL and AR-Vs. AIL down-regulates both AR itself and its target genes in PCa cell lines as well as orthotopic animal tumors. Moreover，AIL directly binds to the co-chaperone protein p23 and prevents AR’s interaction with HSP90, which results 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. Meanwhile, overexpression of p23 dose-dependently rescued AIL-mediated cell proliferation inhibition, suggesting that p23 might be a critical target of AIL. Furthermore, treatment of MDV3100-resistant 22RV1 xenografts with AIL reduced tumor volume by 77.5% (2 mg/kg/day AIL, intraperitoneal) and 79.2% (5 mg/kg/day AIL, oral) compared with the control group. Finally, AIL possesses favorable drug-like properties such as good bioavailability (25.7% F), high solubility, lack of CYP inhibition, and low hepatotoxicity, although signs of gastrointestinal toxicity were observed at high doses. In conclusion, AIL overcomes MDV3100 resistance in castration resistant prostate cancer (CRPC) with excellent absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) properties, thus suggesting that AIL is a potential candidate for the clinical treatment of CRPC.
2016-11-30 | GSE85541 | GEO
Project description:Heat shock protein-90 chaperone machinery is involved in the stability and activity of its client proteins. The chaperone function of Hsp90 is regulated by co-chaperones and post-translational modifications. Although structural evidence exists for Hsp90 interaction with clients, our understanding of the impact of Hsp90 chaperone function towards client activity in cells remains elusive. Here, we dissected the impact of newly identified co-chaperones in higher eukaryotes, FNIP1/2 (FNIPs) and Tsc1, towards Hsp90 client activity. Our data show that Tsc1 and FNIP2 form mutually exclusive complexes with FNIP1 and that unlike Tsc1, FNIP1/2 interact with the catalytic residue of Hsp90. Functionally, these co-chaperone complexes increase the affinity of the steroid hormone receptors glucocorticoid receptor and estrogen receptor to their ligands in vivo. Here, we provide a model for the responsiveness of the steroid hormone receptor activation upon ligand binding as a consequence of their association with specific Hsp90:co-chaperone subpopulations.
2023-05-30 | PXD030486 | Pride
Project description:The efficacy of hormonal therapies for advanced estrogen receptor-positive breast cancers is limited by the nearly inevitable development of acquired resistance. Efforts to block the emergence of resistance have met with limited success, largely because the mechanisms underlying it are so varied and complex. Here, we investigate a new strategy, aimed at the very processes by which cancers evolve resistance. From yeast to vertebrates, HSP90 plays a unique role amongst molecular chaperones by promoting the evolution of heritable new traits. It does so by regulating the folding of a diverse portfolio of metastable client proteins, many of which mediate adaptive responses that allow organisms to adapt and thrive in the face of diverse challenges, including those posed by drugs. Guided by our previous work in pathogenic fungi where very modest HSP90 inhibition impairs resistance to mechanistically diverse antifungals, we examined the effect of similarly modest HSP90 inhibition on the emergence of resistance to anti-estrogens in breast cancer models. Even though this degree of inhibition fell below the threshold for proteotoxic activation of the heat-shock response and had no overt anticancer activity on its own, it dramatically impaired the emergence of resistance to hormone antagonists both in cell culture and in mice. Our findings strongly support the clinical testing of combined hormone antagonist-low level HSP90 inhibitor regimens in the treatment of metastatic ER+ breast cancer. At a broader level, they also provide promising proof-of-principle for a generalizable strategy to combat the pervasive problem of rapidly emerging resistance to molecularly targeted therapeutics.
2014-12-01 | GSE61906 | GEO
Project description:In this study, we used microarray analysis to determine gene expression profile changes in the mouse prostate following castration and hormone replacement. We first identified genes with significant expression changes in each of these two processes and then generated a list of androgen responsive genes and a list of genes whose expression were inversely correlated with the presence of androgen. The analysis of this data set is described in Wang et al., Differentiation, 2006 Keywords: Time course
2006-09-25 | GSE5901 | GEO
Project description:MLL1 WT or KO MEF with and without HSP90 inhibitor treatment
2014-04-15 | GSE56492 | GEO
Project description:A375 cells with inducible knockdown HSF1 with and without HSP90 inhibitor treatment
2013-03-06 | GSE44867 | GEO
Project description:To identify changes at multiple omic levels between hormone naive and castration resistant prostate cancer. Using orthograft murine tumour models of human cell lines injected into the prostate of CD-1 Nude mice grown under castration resistant (castrate) or hormone naive (non-castrate) conditions.
2021-05-03 | E-MTAB-9831 | biostudies-arrayexpress
Project description:Hsp90 is a molecular chaperone involved in the regulation and maturation of kinases and transcription factors. In Caenorhabditis elegans, it contributes to the development of fertility, maintenance of muscle structure, the regulation of heat-shock response and dauer state. To understand the consequences of Hsp90-depletion, we studied Hsp90 RNAi-treated nematodes by DNA microarrays and mass spectrometry. We find that upon development of phenotypes the levels of chaperones and Hsp90 cofactors are increased, while specific proteins related to the innate immune response are depleted. In microarrays, we further find many differentially expressed genes related to gonad and larval development. These genes form an expression cluster that is regulated independently from the immune response implying separate pathways of Hsp90-involvement. Using fluorescent reporter strains for the differentially expressed immune response genes skr-5, dod-24 and clec-60 we observe that their activity in intestinal tissues is influenced by Hsp90-depletion. Instead, effects on the development are evident in both gonad arms. After Hsp90-depletion, changes can be observed in early embryos and adults containing fluorescence-tagged versions of SEPA-1, CAV-1 or PUD-1, all of which are downregulated after Hsp90-depletion. Our observations identify molecular events for Hsp90-RNAi induced phenotypes during development and immune responses, which may help to separately investigate independent Hsp90-influenced processes that are relevant during the nematode’s life and development. We used microarrays to detail the global programme of gene expression after RNAi-mediated Hsp90 knock-down.
2017-10-17 | GSE105030 | GEO