|Wang, Thomas - Tom|
Submitted to: Molecular Cancer Therapeutics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/13/2009
Publication Date: 7/1/2009
Citation: Trasino, S.E., Kim, Y.S., Wang, T.T. 2009. Ligand, receptor, and cell type-dependent regulation of ABCA1 and ABCG1 mRNA in prostate cancer epithelial cells. Molecular Cancer Therapeutics. 8(7):1934-1945. Interpretive Summary: There is substantial evidence that lowering circulating cholesterol levels through diet or with pharmacological agents can lower the risk of developing prostate cancer. The mechanisms are not known but there is evidence that liver x receptors (LXR) in cells can lower cellular cholesterol levels through activation of specific genes (ATP-binding cassette sub family A1 and G1 genes---ABCA1 and ABCG1, respectively). The aim of this study was to test whether activators of LXR in prostate cancer cells can increase the activity of these genes (ABCA1 and ABCG1) known to be involved in the removal of excess cholesterol. Our experiments revealed that LXR activators can increase the activity of these two cholesterol removal genes in two different types of prostate cancer cells. We also demonstrated, however, that the beta, but not the alpha, form of LXR is the major target of control of cholesterol removal genes in these prostate cancel cells. Lastly, we also showed that compounds that activate LXR in these prostate cancer cells can possibly act to increase cellular stress response. This work provides novel information for cancer research scientists regarding molecular targets and mechanism(s) of action that will serve important bases for future investigations of targets of cancer growth and signaling, and will also benefit basic research and applied scientists regarding cholesterol metabolism.
Technical Abstract: Recent evidence suggests that the liver X receptor (LXR) is a potential anti-cancer target in prostate carcinoma. There is little characterization, however, of how the two major isoforms LXRa or LXRß regulate the LXR-responsive genes ATP-binding cassette sub-family A 1 (ABCA1) and sub-family member G 1 (ABCG1) in transformed prostatic epithelial cells. In this study, small interfering RNA (siRNA) was used to determine the role of ABCA1 and ABCG1 mRNA expression after gene silencing of LXRa or LXRß in LNCaP and PC-3 cells. Treatment of both cell lines for 24 hours with the synthetic LXR ligand T0901317 and oxysterols 25-hydroxycholesterol (25HC) and 24(S),25-epoxycholesterol (24,25EC) resulted in more than a ten-fold increase of ABCA1 and ABCG1 mRNA expression. Transfection of LNCaP cells with siRNA against either LXRß or LXRa failed to inhibit T0901317 and 25HC-mediated increases of ABCA1 mRNA. siRNA silencing of LXRß did, however, inhibit ABCA1 mRNA expression in 24,25EC-treated LNCaP cells. In contrast, LXRß 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. Our study is the first to demonstrate that LXRß, but not LXRa,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 p38 MAP kinase signal transduction.