br Conflicts of interest br Acknowledgements This work was s
Conflicts of interest
Acknowledgements This work was supported by the Swiss National Science Foundation No 31003A-179400 to AO. We thank Dr. Thierry Langer, University of Vienna and Inte:Ligand GmbH, for providing the LigandScout Software, and Dr. Daniela Schuster, Paracelsus Medical University Salzburg, for providing GOLD software. We are grateful to Stephane Laurent for technical assistance and to Dr. Carlos Penno for providing input during the initiation of the project.
Introduction Oxysterols are hydroxylated derivatives of cholesterol that play important functions in lipid metabolism and, as signaling-active and mutagenic compounds, received considerable attention in tumor biology . A number of studies revealed that there is no net movement of cholesterol from the peripheral circulation into the CNS and there is general agreement that the Prednisone covers its cholesterol demand by endogenous biosynthesis . Excess brain cholesterol is hydroxylated mainly to 24S-hydroxycholesterol (24S-OHC) and secreted via the blood–brain barrier into the circulation . 24S-OHC is transported in association with lipoproteins and metabolized by the liver . Alternatively, 24S-OHC acts as a bioactive oxysterol in the brain regulating the expression of enzymes involved in cholesterol homeostasis . Apart from 24S-OHC the brain is capable of synthesizing, besides 27-OHC via CYP27A1, 25-OHC via cholesterol 25-hydroxylase (CH25H). CH25H is inducible by interferons  and 25-OHC concentrations are elevated in humans exposed to endotoxin treatment . Two distinct receptor families are represented among the effectors that are known to bind oxysterols, namely the nuclear receptor transcription factors and G protein-coupled seven transmembrane domain receptors. Consequently oxysterols are able to interfere with tumor growth in a dual manner: (i) through regulation of the proinflammatory potential of immune cells by dampening the anti-tumor response of dendritic cells in an liverXreceptor (LXR) dependent manner  or (ii) by recruiting a population of (pro-tumorigenic) immune cells via LXR-independent pathways . 25-OHC is a potent regulator of LXR-mediated pathways, that impact on brain lipid homeostasis . This oxysterol affects expression of the cholesterol efflux pumps ATP-binding cassette transporter (ABC)A1  and ABCG1, and expression of apolipoprotein E , , . 25-OHC is able to stimulate LXR-independent oligodendrocyte apoptosis and suppresses myelin gene expression in peripheral nerves via LXR/Wnt/β-catenin-mediated pathways . LXR-mediated pathways interfere with cholesterol metabolism and, therefore, it is not surprising that oxysterols in the micromolar range are able to inhibit cancer cell proliferation including glioblastoma , breast  and prostate cancer cells  as well as prostate cancer xenografts . LXR agonists interfere with several cell cycle checkpoints inducing cell cycle arrest and phytosterols (plant LXR agonists) were suggested to reduce the incidence of colon cancer . 25-OHC can further act as a negative regulator of sterol regulatory element binding protein (SREBP)-dependent pathways by binding to insulin-induced gene 1 and 2 anchor proteins (Insig1 and -2) thereby inhibiting proteolytic activation of SREBPs . In vitro studies further demonstrated that 20(S)-OHC may also interact with membrane receptors, activating the Hedgehog signaling pathway via binding to the oncoprotein Smoothened . In a similar manner 25-OHC promotes medulloblastoma growth via activation of the Sonic Hedgehog pathway . Conversion of 25-OHC to the more polar 25-OHC-3-sulfate by tumor cells decreases LXR affinity and exerts LXR antagonistic properties via peroxisome proliferator activated receptor (PPAR) γ activation  leading to increased tumor cell growth and tumor immune escape . Glioblastoma multiforme (GBM; astrocytoma grade IV) is the most common and malign primary brain tumor with a mean survival of 14.6 months even under current maximal therapy including surgery and combined chemo- and radiotherapy . Only recently it was demonstrated that the mutated epidermal growth factor receptor (EGFR) present in a high percentage of GBMs overcomes normal cell regulatory mechanisms to feed large amounts of cholesterol to brain cancer cells . We have shown that EGFRvIII upregulates SREBP1 cleavage  and low-density lipoprotein receptor expression, thereby promoting cholesterol uptake, which favors growth and survival of GBM cells . This pathway, which renders tumor cells exquisitely sensitive to LXR agonist-mediated apoptosis , could also feed excess cholesterol into the oxysterol synthesis pathways.