Wood James, Abdelrazig Salah, Evseev Sergey, Ortori Catherine, Castellanos-Uribe Marcos, May Sean T, Barrett David A, Diksin Mohammed, Chakraborty Sajib, Kim Dong-Hyun, Grundy Richard G, Rahman Ruman
Children's Brain Tumour Research Centre, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK.
Centre for Analytical Bioscience, Advanced Materials and Healthcare Technologies Division, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, UK.
Cancers (Basel). 2022 Aug 11;14(16):3873. doi: 10.3390/cancers14163873.
Poor outcomes associated with diffuse high-grade gliomas occur in both adults and children, despite substantial progress made in the molecular characterisation of the disease. Targeting the metabolic requirements of cancer cells represents an alternative therapeutic strategy to overcome the redundancy associated with cell signalling. Cholesterol is an integral component of cell membranes and is required by cancer cells to maintain growth and may also drive transformation. Here, we show that removal of exogenous cholesterol in the form of lipoproteins from culture medium was detrimental to the growth of two paediatric diffuse glioma cell lines, KNS42 and SF188, in association with S-phase elongation and a transcriptomic program, indicating dysregulated cholesterol homeostasis. Interrogation of metabolic perturbations under lipoprotein-deficient conditions revealed a reduced abundance of taurine-related metabolites and cholesterol ester species. Pharmacological reduction in intracellular cholesterol via decreased uptake and increased export was simulated using the liver X receptor agonist LXR-623, which reduced cellular viability in both adult and paediatric models of diffuse glioma, although the mechanism appeared to be cholesterol-independent in the latter. These results provide proof-of-principle for further assessment of liver X receptor agonists in paediatric diffuse glioma to complement the currently approved therapeutic regimens and expand the options available to clinicians to treat this highly debilitating disease.
尽管在弥漫性高级别胶质瘤的分子特征研究方面取得了重大进展，但成人和儿童患者的预后均较差。针对癌细胞的代谢需求是一种替代治疗策略，以克服与细胞信号传导相关的冗余问题。胆固醇是细胞膜的重要组成部分，癌细胞需要它来维持生长，并且可能还会驱动细胞转化。在此，我们表明从培养基中去除脂蛋白形式的外源性胆固醇对两种小儿弥漫性胶质瘤细胞系KNS42和SF188的生长有害，这与S期延长和转录组程序相关，表明胆固醇稳态失调。对脂蛋白缺乏条件下的代谢扰动进行研究发现，与牛磺酸相关的代谢物和胆固醇酯种类的丰度降低。使用肝脏X受体激动剂LXR - 623模拟通过减少摄取和增加输出对细胞内胆固醇进行药理学降低，这在成人和小儿弥漫性胶质瘤模型中均降低了细胞活力，尽管在后者中机制似乎与胆固醇无关。这些结果为进一步评估肝脏X受体激动剂在小儿弥漫性胶质瘤中的作用提供了原理证明，以补充目前批准的治疗方案，并为临床医生治疗这种极具致残性的疾病扩展可用选项。
