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Generation 2.5 antisense oligonucleotides targeting the androgen receptor and its splice variants suppress enzalutamide-resistant prostate cancer cell growth
- Source :
- Clinical cancer research : an official journal of the American Association for Cancer Research. 21(7)
- Publication Year :
- 2014
-
Abstract
- Purpose: 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. Experimental Design: 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 ARFL alone or with AR-Vs, and examined their effects in three CRPC cell lines and patient-derived xenografts. Results: ENZ-R-LNCaP cells express high levels of both ARFL and AR-V7 compared with CRPC-LNCaP; in particular, ARFL levels were approximately 12-fold higher than AR-V7. Both ARFL and AR-V7 are highly expressed in the nuclear fractions of ENZ-R-LNCaP cells even in the absence of exogenous androgens. 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, and delayed tumor growth in vivo. In 22Rv1 cells that are inherently ENZ-resistant, 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. Exon-1 AR-ASO also inhibited tumor growth of LTL-313BR patient-derived CRPC xenografts. Conclusions: These data identify the AR as 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. Clin Cancer Res; 21(7); 1675–87. ©2015 AACR.
- Subjects :
- Male
Cancer Research
medicine.medical_specialty
Cell
Blotting, Western
Antineoplastic Agents
urologic and male genital diseases
Transfection
Prostate cancer
chemistry.chemical_compound
Mice
Internal medicine
LNCaP
Nitriles
Phenylthiohydantoin
medicine
Enzalutamide
Animals
Humans
Protein Isoforms
RNA, Small Interfering
Gene knockdown
Cell growth
Chemistry
Reverse Transcriptase Polymerase Chain Reaction
Oligonucleotides, Antisense
medicine.disease
Immunohistochemistry
Xenograft Model Antitumor Assays
Androgen receptor
Prostatic Neoplasms, Castration-Resistant
Endocrinology
medicine.anatomical_structure
Oncology
Drug Resistance, Neoplasm
Receptors, Androgen
Benzamides
Cancer research
Subjects
Details
- ISSN :
- 15573265
- Volume :
- 21
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Accession number :
- edsair.doi.dedup.....abb20401b22d809b403ec914a94cd469