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Series GSE55345 Query DataSets for GSE55345
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
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.
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.
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
Organization name Vancouver Prostate Centre
Lab Laboratory for Advanced Genome Analysis
Street address 2660 Oak Street
City Vancouver
State/province BC
ZIP/Postal code V6H3Z6
Country Canada
Platforms (1)
GPL10123 Agilent-022060 SurePrint G3 Human CGH Microarray 4x180K (Feature Number version)
Samples (6)
GSM1334479 P111_ENZ-R
GSM1334480 P145_ENZ-R
GSM1334481 P163_ENZ-R
BioProject PRJNA239365

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

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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