Department of Anatomical Pathology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Av. Tessália Vieira de Camargo, 126, Campinas, SP, Zip Code: 13083-887, Brazil.
Department of Clinical Pathology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Av. Tessália Vieira de Camargo, 126, Campinas, SP, Zip Code: 13083-887, Brazil.
J Neurooncol. 2018 Feb;136(3):435-443. doi: 10.1007/s11060-017-2672-9. Epub 2017 Nov 20.
Glioblastoma (GBM) is the most common primary brain tumor. Genetic mutations may reprogram the metabolism of neoplastic cells. Particularly, alterations in cholesterol and fatty acid biosynthetic pathways may favor biomass synthesis and resistance to therapy. Therefore, compounds that interfere with those pathways, such as phytol (PHY) and retinol (RET), may be appropriate for cytotoxic approaches. We tested the effect of PHY or RET on the viability of human GBM cell lines (U87MG, A172 and T98G). Since the compounds showed a dose-dependent cytotoxic effect, additional analyses were performed with IC values. Transcriptome analyses of A172 cells treated with PHY IC or RET IC revealed down-regulated genes involved in cholesterol and/or fatty acid biosynthetic pathways. Thus, we investigated the expression of proteins required for cholesterol and/or fatty acid synthesis after treating all lineages with PHY IC or RET IC and comparing them with controls. Sterol regulatory element-binding protein 1 (SREBP-1) expression was reduced by PHY in U87 and T98G cells. However, fatty acid synthase (FAS) protein expression, which is regulated by SREBP-1, was down-regulated in all lineages after both treatments. Moreover, farnesyl-diphosphate farnesyltransferase (FDFT1) levels, a protein associated with cholesterol synthesis, were reduced in all lineages by PHY and in U87MG and A172 cells by RET. Our results suggest that SREBP-1, FAS and FDFT1 are potential target(s) for future in vivo approaches against GBM and support the use of inhibitors of their synthesis, including PHY and RET, for such approaches.
胶质母细胞瘤（GBM）是最常见的原发性脑肿瘤。遗传突变可能会重新编程肿瘤细胞的代谢。特别是胆固醇和脂肪酸生物合成途径的改变可能有利于生物量合成和对治疗的抵抗。因此，干扰这些途径的化合物，如叶绿醇（PHY）和视黄醇（RET），可能适用于细胞毒性方法。我们测试了 PHY 或 RET 对人 GBM 细胞系（U87MG、A172 和 T98G）活力的影响。由于这些化合物表现出剂量依赖性的细胞毒性作用，因此使用 IC 值进行了额外的分析。用 PHY IC 或 RET IC 处理 A172 细胞的转录组分析显示，参与胆固醇和/或脂肪酸生物合成途径的下调基因。因此，在用 PHY IC 或 RET IC 处理所有细胞系并与对照比较后，我们研究了胆固醇和/或脂肪酸合成所需蛋白的表达。PHY 在 U87 和 T98G 细胞中降低了固醇调节元件结合蛋白 1（SREBP-1）的表达。然而，在两种处理后，所有细胞系中的脂肪酸合酶（FAS）蛋白表达均下调，而 FAS 蛋白表达受 SREBP-1 调控。此外，与胆固醇合成相关的蛋白质法尼基二磷酸法尼基转移酶（FDFT1）水平在所有细胞系中均被 PHY 降低，在 U87MG 和 A172 细胞中也被 RET 降低。我们的结果表明，SREBP-1、FAS 和 FDFT1 可能是未来针对 GBM 的体内方法的潜在靶标，并支持使用其合成抑制剂，包括 PHY 和 RET，进行此类方法。
