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Cotargeting Androgen Receptor and Clusterin Delays Castrate-Resistant Prostate Cancer Progression by Inhibiting Adaptive Stress Response and AR Stability.
- Source :
-
Cancer research [Cancer Res] 2013 Aug 15; Vol. 73 (16), pp. 5206-17. Date of Electronic Publication: 2013 Jun 20. - Publication Year :
- 2013
-
Abstract
- Although androgen receptor (AR) pathway inhibitors prolong survival in castrate-resistant prostate cancer (CRPC), resistance rapidly develops and is often associated with increased stress-activated molecular chaperones like clusterin (CLU) and continued AR signaling. Because adaptive pathways activated by treatment facilitate development of acquired resistance, cotargeting the stress response, activated by AR inhibition and mediated through CLU, may create conditional lethality and improve outcomes. Here, we report that CLU is induced by AR antagonism and silencing using MDV3100 and antisense, respectively, to become highly expressed in castrate- and MDV3100-resistant tumors and cell lines. CLU, as well as AKT and mitogen-activated protein kinase (MAPK) signalosomes, increase in response to MDV3100-induced stress. Mechanistically, this stress response is coordinated by a feed-forward loop involving p90rsk (RPS6KA)-mediated phosphoactivation of YB-1 with subsequent induction of CLU. CLU inhibition repressed MDV3100-induced activation of AKT and MAPK pathways. In addition, when combined with MDV3100, CLU knockdown accelerated AR degradation and repressed AR transcriptional activity through mechanisms involving decreased YB-1-regulated expression of the AR cochaperone, FKBP52. Cotargeting the AR (with MDV3100) and CLU (with OGX-011) synergistically enhanced apoptotic rates over that seen with MDV3100 or OGX-011 monotherapy and delayed CRPC LNCaP tumor and prostate-specific antigen (PSA) progression in vivo. These data indicate that cotargeting adaptive stress pathways activated by AR pathway inhibitors, and mediated through CLU, creates conditional lethality and provides mechanistic and preclinical proof-of-principle to guide biologically rational combinatorial clinical trial design.
- Subjects :
- Animals
Apoptosis drug effects
Apoptosis genetics
Benzamides
Castration methods
Cell Line, Tumor
Disease Progression
Gene Expression Regulation, Neoplastic drug effects
Gene Expression Regulation, Neoplastic genetics
Gene Silencing drug effects
Humans
Male
Mice
Mice, Nude
Mitogen-Activated Protein Kinases genetics
Mitogen-Activated Protein Kinases metabolism
Molecular Chaperones genetics
Molecular Chaperones metabolism
Nitriles
Phenylthiohydantoin analogs & derivatives
Phenylthiohydantoin pharmacology
Prostate-Specific Antigen genetics
Prostate-Specific Antigen metabolism
Prostatic Neoplasms, Castration-Resistant drug therapy
Prostatic Neoplasms, Castration-Resistant genetics
Prostatic Neoplasms, Castration-Resistant metabolism
Proteasome Endopeptidase Complex genetics
Proteasome Endopeptidase Complex metabolism
Proto-Oncogene Proteins c-akt genetics
Proto-Oncogene Proteins c-akt metabolism
Signal Transduction drug effects
Signal Transduction genetics
Stress, Physiological genetics
Tacrolimus Binding Proteins genetics
Tacrolimus Binding Proteins metabolism
Thionucleotides pharmacology
Transcription, Genetic drug effects
Transcription, Genetic genetics
Clusterin genetics
Clusterin metabolism
Prostatic Neoplasms, Castration-Resistant pathology
Receptors, Androgen genetics
Receptors, Androgen metabolism
Stress, Physiological drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 73
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 23786771
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-13-0359