Androgen-mediated cholesterol metabolism in LNCaP and PC-3 cell lines is regulated through two different isoforms of acyl-coenzyme A:Cholesterol Acyltransferase (ACAT)

Prostate. 2008 Jan 1;68(1):20-33. doi: 10.1002/pros.20674.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgens / agonists
  • Androgens / metabolism*
  • Cell Line, Tumor
  • Cholesterol / metabolism*
  • Cholesterol Esters / metabolism
  • Esterification
  • Humans
  • Hydroxymethylglutaryl CoA Reductases / metabolism
  • Interferon-Stimulated Gene Factor 3 / metabolism
  • Isoenzymes / metabolism
  • Male
  • Metribolone / pharmacology
  • Microsomes / enzymology
  • Phosphorylation
  • Prostate / enzymology
  • Prostatic Neoplasms / metabolism*
  • Receptors, Androgen / metabolism
  • Sterol O-Acyltransferase / metabolism*

Substances

  • Androgens
  • Cholesterol Esters
  • Interferon-Stimulated Gene Factor 3
  • Isoenzymes
  • Receptors, Androgen
  • gamma interferon activation factor
  • Metribolone
  • Cholesterol
  • Hydroxymethylglutaryl CoA Reductases
  • Sterol O-Acyltransferase
  • sterol O-acyltransferase 1
  • sterol O-acyltransferase 2