Androgen-mediated cholesterol metabolism in LNCaP and PC-3 cell lines is regulated through two different isoforms of acyl-coenzyme A:Cholesterol Acyltransferase (ACAT).
BACKGROUND
The objective of this work was to determine the effect of an androgen agonist, R1881, on intracellular cholesterol synthesis and esterification in androgen-sensitive (AS) prostate cancer (LNCaP) cells.


METHODS
We investigated the activity and expression of cholesterol metabolism enzymes, HMG-CoA-reductase and ACAT in the LNCaP and PC-3 (androgen-independent control) models.


RESULTS
Microsomal PC-3 HMG-CoA-reductase activity was increased with R1881 despite having similar cholesterol levels while increased cholesterol levels in microsomes from LNCaPs treated with R1881 (L+) were associated with increased HMG-CoA reductase activity. Increased intracellular cholesteryl esters (CE) found in (L+) were not associated with an increased ACAT1 activity. There was no effect from androgen treatment on ACAT1 protein expression in theses cells; however, ACAT2 expression was induced upon R1881 treatment. In contrast, we found an increase in the in vitro ACAT1 activity in PC-3 cells treated with androgen (P+). Only ACAT1 expression was induced in P+. We further assessed the expression of STAT1 alpha, a transcriptional activator that modulates ACAT1 expression. STAT1 alpha expression and phosphorylation were induced in P+. To determine the role of the AR on ACAT1 expression and esterification, we treated PC-3 cells overexpressing the androgen receptor with R1881 (PAR+). AR expression was decreased in PAR+ cells; ACAT1 protein expression and cholesterol ester levels were also decreased, however, ACAT2 remained unchanged. STAT1 alpha expression was decreased in PAR+.


CONCLUSIONS
Overall, these findings support the importance of cholesterol metabolism regulation within prostate cancer cells and unravel a novel role for STAT1 alpha in prostate cancer metabolism.
Locke
Jennifer A
JA
Department of Urologic Sciences, University of British Columbia, The Prostate Centre at Vancouver General Hospital, Vancouver, British Columbia, Canada.
Wasan
Kishor M
KM
Nelson
Colleen C
CC
Guns
Emma S
ES
Leon
Carlos G
CG
D000728:Androgens / Q000819:agonists / Q000378:metabolism*; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism*; D002788:Cholesterol Esters / Q000378:metabolism; D004951:Esterification; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D050832:Interferon-Stimulated Gene Factor 3 / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D008861:Microsomes / Q000201:enzymology; D010766:Phosphorylation; D011467:Prostate / Q000201:enzymology; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism; D002785:Sterol O-Acyltransferase / Q000378:metabolism*; D000097587:Sterol O-Acyltransferase 2
D000728:Androgens; D002784:Cholesterol; D002788:Cholesterol Esters; D006903:Hydroxymethylglutaryl CoA Reductases; D050832:Interferon-Stimulated Gene Factor 3; D007527:Isoenzymes; D015741:Metribolone; D011944:Receptors, Androgen; D002785:Sterol O-Acyltransferase; D000097587:Sterol O-Acyltransferase 2; C079868:gamma interferon activation factor; C493492:sterol O-acyltransferase 1