In the latter model, both LXRα and -β isoforms were involved [48]. Yet, in this model, LXR activation reduced the expression of Skp2 and cyclin D1. Importantly, these effects were obtained with synthetic LXR agonists as well as with naturally occurring oxysterols. Similar results have also been reported in T- and B-CLL cell growth [29]. In T-CLL lines, Geyeregger et al. reported that LXR activation inhibits retinoblastoma protein phosphorylation and downregulates the expression of the cyclin B protein. In B-CLL cells, LXR activation was found to inhibit the expression of Bcl2 and MMP-9, thus reducing cell viability [29]
(Fig. 2A). The levels of circulating cholesterol were found to be higher n Lxra−/−Lxrβ−/− mice fed with a high-cholesterol diet than in BAY 57-1293 WT control mice. This resulted in cholesterol ester accumulation and development of prostatic intraepithelial neoplasia [49]. The accumulation of cholesterol esters, due to decreased expression of the transporter in charge of cholesterol efflux (i.e., ABCA1) and increased expression of the low density lipoprotein receptor in the absence of LXR
signaling, was linked to the increased expression of the histone methyl transferase enhancer of zeste homolog 2 . Enhancer of zeste homolog 2 increased the methylation of lysine 27 of histone H3 (H3K27) on the promoters of the tumor suppressor genes beta-microseminoprotein Doxorubicin cell line (Msmb) and homeobox protein NKX3.1 (Nkx3.1), whose expression turned out to be downregulated. The downregulation of the above-mentioned tumor suppressor genes, mediated by the accumulation of cholesterol esters in the absence
of LXR signaling, could be responsible for prostate tumorigenesis [49]. Differently from the previous model, LNCaP prostate Reverse transcriptase tumor cells stimulated with synthetic LXR agonists showed G1 to S-phase cell cycle arrest through the suppression of Skp2 [50], as reported for breast and colon cancer cells. Furthermore, LXR activation also promotes apoptosis of LNCaP cells through the disruption of the signaling mediated by lipid rafts [51]. This mechanism relies on the reduction of both membrane cholesterol content and phosphorylated fraction of AKT associated with lipid rafts. Of note, these effects are also active in vivo in immunodeficient mice xenografted with LNCaP cells and treated with synthetic LXR agonists [51]. In GBM, it has been shown that EGFRvIII promotes tumor survival through PI3K/sterol response element-binding protein-1-dependent upregulation of low density lipoprotein receptor (LDLR) [52]. The growth of GBM was inhibited in vivo by synthetic LXR agonist treatment, which caused inducible degrader of LDLR-mediated LDLR degradation and increased expression of the ABCA1 transporter [52].