Second-Generation HSP90 Inhibitor Onalespib Blocks mRNA Splicing of Androgen Receptor Variant 7 in Prostate Cancer Cells.
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Date
2016-05-01ICR Author
Author
Ferraldeschi, R
Welti, J
Powers, MV
Yuan, W
Smyth, T
Seed, G
Riisnaes, R
Hedayat, S
Wang, H
Crespo, M
Nava Rodrigues, D
Figueiredo, I
Miranda, S
Carreira, S
Lyons, JF
Sharp, S
Plymate, SR
Attard, G
Wallis, N
Workman, P
de Bono, JS
Type
Journal Article
Metadata
Show full item recordAbstract
Resistance to available hormone therapies in prostate cancer has been associated with alternative splicing of androgen receptor (AR) and specifically, the expression of truncated and constitutively active AR variant 7 (AR-V7). The transcriptional activity of steroid receptors, including AR, is dependent on interactions with the HSP90 chaperone machinery, but it is unclear whether HSP90 modulates the activity or expression of AR variants. Here, we investigated the effects of HSP90 inhibition on AR-V7 in prostate cancer cell lines endogenously expressing this variant. We demonstrate that AR-V7 and full-length AR (AR-FL) were depleted upon inhibition of HSP90. However, the mechanisms underlying AR-V7 depletion differed from those for AR-FL. Whereas HSP90 inhibition destabilized AR-FL and induced its proteasomal degradation, AR-V7 protein exhibited higher stability than AR-FL and did not require HSP90 chaperone activity. Instead, HSP90 inhibition resulted in the reduction of AR-V7 mRNA levels but did not affect total AR transcript levels, indicating that HSP90 inhibition disrupted AR-V7 splicing. Bioinformatic analyses of transcriptome-wide RNA sequencing data confirmed that the second-generation HSP90 inhibitor onalespib altered the splicing of at least 557 genes in prostate cancer cells, including AR. These findings indicate that the effects of HSP90 inhibition on mRNA splicing may prove beneficial in prostate cancers expressing AR-V7, supporting further clinical investigation of HSP90 inhibitors in malignancies no longer responsive to androgen deprivation. Cancer Res; 76(9); 2731-42. ©2016 AACR.
Subject
Cell Line, Tumor
Animals
Humans
Mice
Prostatic Neoplasms
Benzamides
Receptors, Androgen
RNA, Messenger
Blotting, Western
Immunohistochemistry
Xenograft Model Antitumor Assays
Polymerase Chain Reaction
Immunoprecipitation
RNA Splicing
Drug Resistance, Neoplasm
Male
HSP90 Heat-Shock Proteins
Isoindoles
Research team
Target Evaluation and Molecular Therapeutics
Cancer Biomarkers
Prostate Cancer Targeted Therapy Group
Functional Genomics
Treatment Resistance
Language
eng
Date accepted
2016-01-27
License start date
2016-05
Citation
Cancer research, 2016, 76 (9), pp. 2731 - 2742
Publisher
AMER ASSOC CANCER RESEARCH