Ligand, receptor, and cell type–dependent regulation ofABCA1andABCG1mRNA in prostate cancer epithelial cells

Abstract

Recent evidence suggests that the liver X receptor (LXR) is a potential anticancer target in prostate carcinoma. There is little characterization, however, of which of the two LXR isoforms, LXRα or LXRβ, regulates the LXRresponsive genes ATP-binding cassette subfamily members A1 (ABCA1) and G1 (ABCG1) in transformed prostatic epithelial cells. In this study, small interfering RNA (siRNA) was used to determine whether LXRα or LXRβ is involved in regulating ABCA1 and ABCG1 mRNA expression in LNCaP and PC-3 cells. Treatment of both cell lines with the synthetic LXR ligand T0901317 and oxysterols: 25-hydroxycholesterol (25HC) and 24(S), 25-epoxycholesterol (24,25EC), resulted in more than a 10-fold increase of ABCA1 and ABCG1 mRNA expression. Transfection of LNCaP cells with siRNA against either LXRβ or LXRα failed to inhibit T0901317 and 25HC-mediated increase of ABCA1 mRNA. siRNA silencing of LXRβ did, however, inhibit ABCA1 mRNA expression in 24,25EC-treated LNCaP cells. In contrast, LXRβ siRNA inhibited T0901317, 25HC, and 24,25EC induction of ABCA1 mRNA in PC-3 cells and ABCG1 mRNA in both LNCaP and PC-3 cells. Additional experiments revealed that T0901317 and 25HC induction of ABCA1 mRNA expression was significantly inhibited by the p38 stress kinase antagonist SB202190 and PKA inhibitor H89. Our study is the first to show that LXRβ, but not LXRα, is the major regulatory isoform of ABCG1 mRNA expression in LNCaP and PC-3 cells. Our study also reveals that ABCA1 gene expression is differentially regulated by synthetic and natural LXR ligands, possibly involving kinase mediated signal transduction.

Dysregulation of Cholesterol Homeostasis in Human Prostate Cancer through Loss of ABCA1

“…Again, demethylation of the ABCA1 promoter with 5-aza followed by treatment with T0901317 resulted in robust ABCA1 protein expression in LNCaP. It is worth noting that minimal ABCA1 expression and severely limited induction by trans-activators in LNCaP cells have been independently reported by other groups without a mechanistic explanation (14, 21, 22). …”

Liver X Receptors Protect from Development of Prostatic Intra-Epithelial Neoplasia in Mice

“…Absence of any change in LXRα expression could explain the lack of a clear deregulation of some LXR target genes in Oncomine datasets (data not shown). Moreover, both LXRα and LXRβ have been demonstrated to be expressed and functional in human PCa cells [8], [38]. These observations suggest that EZH2 deregulation could be linked to a mechanism specifically depending on LXRβ.…”

Quercetin enhances ABCA1 expression and cholesterol efflux through a p38-dependent pathway in macrophages

“…Moreover, we showed that the quercetin-induced binding of Sp1 to the ABCA1 promoter is suppressed in the p38 knockdown cells. A recent study has shown that a p38 inhibitor, SB202190, inhibits the induction of ABCA1 mRNA expression by LXR ligand in prostate cancer epithelial cells (49), implying that p38 could regulate LXR-mediated gene transcription. We also found that the quercetin-induced binding of LXRα to the ABCA1 promoter was attenuated in p38 knockdown RAW264.7 macrophages.…”