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

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 (Lþ) were associated with increased HMG-CoA reductase activity. Increased intracellular cholesteryl esters (CE) found in (Lþ) 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 (Pþ). Only ACAT1 expression was induced in Pþ. We further assessed the expression of STAT1a, a transcriptional activator that modulates ACAT1 expression. STAT1a expression and phosphorylation were induced in Pþ. To determine the role of the AR on ACAT1 expression and esterification, we treated PC-3 cells overexpressing the androgen receptor with R1881 (PARþ). AR expression was decreased in PARþ cells; ACAT1 protein expression and cholesterol ester levels were also decreased, however, ACAT2 remained unchanged. STAT1a expression was decreased in PARþ. CONCLUSIONS. Overall, these findings support the importance of cholesterol metabolism regulation within prostate cancer cells and unravel a novel role for STAT1a in prostate cancer metabolism.

Exosomes as Biomarker Enriched Microvesicles: Characterization of Exosomal Proteins Derived from a Panel of Prostate Cell Lines with Distinct AR Phenotypes

“…Interestingly our quantitative cholesterol data suggests that exosomes derived from PCa cell lines contain significantly more cholesterol than their benign counterpart cell line RWPE-1. This is in line with our previous work which indicates that cholesterol is likely to play a role in PCa progression (70,71).…”

Quantitative Proteomics Reveals That Enzymes of the Ketogenic Pathway Are Associated with Prostate Cancer Progression

“…With the exception of ACAT1, the ketogenesis pathway has not been investigated in prostate cancer. Specifically, ACAT1 was shown to be involved in the androgen-mediated cholesterol metabolism in prostate cancer cell lines (56). In another recent study, ACAT1 protein expression was found to be elevated in LNCaP androgen-independent xenografts, further suggesting its importance during prostate cancer progression (57).…”

Anticancer Efficacy of Simvastatin on Prostate Cancer Cells and Tumor Xenografts Is Associated with Inhibition of Akt and Reduced Prostate-Specific Antigen Expression

“…Cholesterol-lowering effects of statins are believed to be a very important factor in the regulation of prostate cancer cell functions. Androgens are known to mediate cholesterol metabolism in LNCaP cells involving Acyl-CoA cholesterol acyltransferase facilitating tumor progression (Locke et al, 2008). Previous studies have shown that prostate cancer cells lack a sterol-mediated feedback regulation of the sterol regulatory element-binding protein-2 (SREBP-2), a transcription factor regulating cholesterol homeostasis (Krycer et al, 2009), in LNCaP and PC3 cells.…”