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  • (3S,5S)-Atorvastatin sodium salt receptor OHC is a potent re


    25-OHC is a potent regulator of LXR-mediated pathways, that impact on (3S,5S)-Atorvastatin sodium salt receptor lipid homeostasis [8]. This oxysterol affects expression of the cholesterol efflux pumps ATP-binding cassette transporter (ABC)A1 [9] and ABCG1, and expression of apolipoprotein E [10], [11], [12]. 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 [13]. 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 [14], breast [15] and prostate cancer cells [16] as (3S,5S)-Atorvastatin sodium salt receptor well as prostate cancer xenografts [17]. 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 [18]. 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 [19]. 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 [20]. In a similar manner 25-OHC promotes medulloblastoma growth via activation of the Sonic Hedgehog pathway [21]. 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 [22] leading to increased tumor cell growth and tumor immune escape [23]. 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 [24]. 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 [13]. We have shown that EGFRvIII upregulates SREBP1 cleavage [25] and low-density lipoprotein receptor expression, thereby promoting cholesterol uptake, which favors growth and survival of GBM cells [14]. This pathway, which renders tumor cells exquisitely sensitive to LXR agonist-mediated apoptosis [13], could also feed excess cholesterol into the oxysterol synthesis pathways. Oxysterols modulate the immune responses and as such could be effectors of the tumor environment: 25-OHC impairs IgA production in B-lymphocytes [26] and induces the secretion of the proinflammatory and angiogenic cytokine IL-8 [27], [28]. Of note, oxysterols (in particular 7α,25-OHC) are potent chemoattractants for immune cells via Epstein-Barr virus-induced G protein-coupled receptor 2 (EBI2; also termed GPR183) [29], [30]. Besides regulating normal function of the immune system this pathway might be of importance in the tumor environment, contributing to chemotactic recruitment of monocytes across the tumor vasculature and subsequent deposition of tumor-associated macrophages. The present study aimed at investigating CH25H expression on mRNA and protein level in two GBM cell lines with different in silico CH25H mRNA expression ( We explored the effects of TNFα and IL-1β (cytokines secreted by GBM cells [31], [32], [33]) on CH25H transcription and translation, and quantitated its product 25-OHC by GC–MS analysis. Using THP-1 and primary human blood monocytes we studied the effects of exogenous 25-OHC and GBM-conditioned medium on cell migration, since monocyte-derived macrophages are known to contribute to increased aggressiveness and invasiveness of glioblastoma [34]. Finally, the involvement of the G protein-coupled receptor EBI2 in 25-OHC-mediated migration of THP-1 cells was investigated.