Alterations in cholesterol regulation contribute to the production of intratumoral androgens during progression to castration-resistant prostate cancer in a mouse xenograft model

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 docu...

Full description

Saved in:
Bibliographic Details
Published in:The Prostate 2010-03, Vol.70 (4), p.390-400
Main Authors: Leon, Carlos G., Locke, Jennifer A., Adomat, Hans H., Etinger, Susan L., Twiddy, Alexis L., Neumann, Rachel D., Nelson, Colleen C., Guns, Emma S., Wasan, Kishor M.
Format: Article
Language:English
Subjects:
Acetyl-CoA C-Acetyltransferase - metabolism
androgens
Androgens - biosynthesis
Animals
Biological and medical sciences
castration-resistance
Cholesterol - metabolism
cholesterol cellular influx and efflux
cholesterol synthesis
Chromatography, High Pressure Liquid
Disease Progression
Gene Expression Regulation, Neoplastic
Gynecology. Andrology. Obstetrics
Homeostasis
Hydroxymethylglutaryl CoA Reductases - metabolism
Male
Male genital diseases
Mass Spectrometry
Medical sciences
Membrane Proteins - metabolism
Mice
Nephrology. Urinary tract diseases
Orchiectomy
prostate cancer
Prostate-Specific Antigen - genetics
Prostate-Specific Antigen - metabolism
Prostatic Neoplasms - genetics
Prostatic Neoplasms - metabolism
Prostatic Neoplasms - pathology
Receptors, Androgen - metabolism
RNA, Messenger - metabolism
Tumors
Tumors of the urinary system
Urinary tract. Prostate gland
Xenograft Model Antitumor Assays
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. Prostate 70: 390–400, 2010. © 2009 Wiley‐Liss, Inc.
ISSN:0270-4137
1097-0045
DOI:10.1002/pros.21072