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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Jan 01, 2015 |
| Title |
Generation 2.5 Antisense Oligonucleotides Targeting the Androgen Receptor and its Splice Variants Suppress Enzalutamide-Resistant Prostate Cancer Cell Growth |
| Organism |
Homo sapiens |
| Experiment type |
Genome variation profiling by genome tiling array
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| Summary |
Enzalutamide (ENZ) is a potent androgen receptor (AR) antagonist with activity in castration-resistant prostate cancer (CRPC); however, progression to ENZ-resistant (ENZ-R) CRPC frequently occurs with rising serum PSA levels, implicating AR full length (ARFL) or variants (AR-Vs) in disease progression. To define functional roles of ARFL and AR-Vs in ENZ-R CRPC, we designed 3 antisense oligonucleotides (ASO) targeting exon 1, intron 1, and exon 8 in AR pre-mRNA to knockdown either ARFL alone, or ARFL plus AR-Vs, and examined their respective effects in LNCaP-derived ENZ-R, as well as M12 and 22Rv1, cells. ENZ-R LNCaP xenografts express high levels of both ARFL and AR-V7 compared to CRPC LNCaP xenografts. In particular, ARFL levels were ~20-fold higher than AR-V7. ENZ-R LNCaP sub-lines, derived by selection from the ENZ xenografts, also expressed uniformly high levels of ARFL and AR-V7 compared to CRPC LNCaP cells. In addition, both ARFL and AR-V7 are highly expressed in the nuclear fractions of ENZ-R-LNCaP. In ENZ-R LNCaP cells, knockdown of ARFL alone, or ARFL plus AR-Vs, similarly induced apoptosis, suppressed cell growth and AR-regulated gene expression in vitro, and delayed tumour growth in vivo. In 22Rv1 cells that are inherently resistant to ENZ, knockdown of both ARFL and AR-Vs more potently suppressed cell growth, AR transcriptional activity and AR-regulated gene expression than knockdown of ARFL alone. These data indicate the AR is an important driver of ENZ resistance, and while the contributions of ARFL and AR-Vs can vary across cell systems, ARFL is the key driver in the ENZ-R LNCaP model. AR targeting strategies against both ARFL and AR-Vs is a rational approach for AR-dependent CRPC.
CRPC and ENZ-R LNCaP xenografts were generated as described in: Gleave, M.E., et al., Serum prostate specific antigen levels in mice bearing human prostate LNCaP tumors are determined by tumor volume and endocrine and growth factors. Cancer Res, 1992. 52(6): p. 1598-605.
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| Overall design |
6 samples were analyzed: 2 control castrate-resistant prostate cancer cell line xenografts and 4 castrate-resistant prostate cancer cell line xenografts treated with Enzalutamide until resistance emerged. Samples were competitively hybridized against a male reference pool using Agilent aCGH arrays.
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| Contributor(s) |
Yamamoto Y, Wyatt AW, Gleave M |
| Citation(s) |
25634993 |
| Submission date |
Feb 25, 2014 |
| Last update date |
Apr 02, 2015 |
| Contact name |
Shawn Anderson |
| E-mail(s) |
Sanderson@prostatecentre.com
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| Organization name |
Vancouver Prostate Centre
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| Lab |
Laboratory for Advanced Genome Analysis
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| Street address |
2660 Oak Street
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| City |
Vancouver |
| State/province |
BC |
| ZIP/Postal code |
V6H3Z6 |
| Country |
Canada |
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| Platforms (1) |
| GPL10123 |
Agilent-022060 SurePrint G3 Human CGH Microarray 4x180K (Feature Number version) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA239365 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE55345_RAW.tar |
113.5 Mb |
(http)(custom) |
TAR (of TXT) |
| Processed data included within Sample table |
| Processed data provided as supplementary file |
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