| Alterations in cholesterol regulation contribute to the production of intratumoral androgens during progression to castration-resistant prostate cancer in a mouse xenograft model. | |
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MedLine Citation:
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PMID: 19866465 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: Emerging evidence suggests that androgens and the androgen receptor (AR) are important mediators of castration-resistant prostate cancer (CRPC) progression. Increased expression of several enzymes responsible for cholesterol synthesis and conversion into downstream androgens has been documented in human CRPC tumors in comparison to primary tumors. Based on these observations it is hypothesized that cholesterol and its overall regulation within the cell are altered, thus modifying precursor levels for de novo androgen synthesis within the castrate tumoral environment. METHODS: Tumoral steroid levels were assessed by LC-MS. Free and esterified cholesterol was quantified by LC-MS and a fluorescent assay. Gene and protein expression were assessed by RT-PCR and immunoblotting. RESULTS: Herein, using a prostate cancer xenograft mouse model it is demonstrated by Western blot analysis that proteins responsible for cholesterol regulation (LDL-r, SR-B1, HMG-CoA reductase, ACAT1,2, ABCA1) are altered during disease progression to increase influx and synthesis of cholesterol as well as free cholesterol formation from cholesteryl ester stores. In turn this can provide increased amounts of precursor for intratumoral steroidogenesis after castration. Androgens- testosterone and dihydrotestosterone- coincidently increase at CRPC to physiologically relevant levels leading to the induction of AR expression and PSA production. Furthermore, cellular cholesterol homeostasis is maintained by increased cholesterol efflux at CRPC so that excess free cholesterol does not cause toxicity to the tumor cells. CONCLUSIONS: Cellular cholesterol regulation processes are altered during progression to CRPC. Free cholesterol from increased biosynthesis or uptake is likely a precursor for intratumoral de novo androgen synthesis. |
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Authors:
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Carlos G Leon; Jennifer A Locke; Hans H Adomat; Susan L Etinger; Alexis L Twiddy; Rachel D Neumann; Colleen C Nelson; Emma S Guns; Kishor M Wasan |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: The Prostate Volume: 70 ISSN: 1097-0045 ISO Abbreviation: Prostate Publication Date: 2010 Mar |
Date Detail:
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Created Date: 2010-02-03 Completed Date: 2010-02-23 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8101368 Medline TA: Prostate Country: United States |
Other Details:
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Languages: eng Pagination: 390-400 Citation Subset: IM |
Copyright Information:
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Prostate 70: 390-400, 2010. (c) 2009 Wiley-Liss, Inc. |
Affiliation:
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Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada. cleon@interchange.ubc.ca |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Acetyl-CoA C-Acetyltransferase
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metabolism Androgens / biosynthesis* Animals Cholesterol / metabolism* Chromatography, High Pressure Liquid Disease Progression Gene Expression Regulation, Neoplastic Homeostasis Hydroxymethylglutaryl CoA Reductases / metabolism Male Mass Spectrometry Membrane Proteins / metabolism Mice Orchiectomy Prostate-Specific Antigen / genetics, metabolism Prostatic Neoplasms / genetics, metabolism, pathology* RNA, Messenger / metabolism Receptors, Androgen / metabolism* Xenograft Model Antitumor Assays |
| Grant Support | |
ID/Acronym/Agency:
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//Canadian Institutes of Health Research |
| Chemical | |
Reg. No./Substance:
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0/Androgens; 0/Membrane Proteins; 0/RNA, Messenger; 0/Receptors, Androgen; 57-88-5/Cholesterol; EC 1.1.1.-/Hydroxymethylglutaryl CoA Reductases; EC 2.3.1.9/Acetyl-CoA C-Acetyltransferase; EC 3.4.21.77/Prostate-Specific Antigen |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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