Targeting cholesterol metabolism in glioblastoma: a new therapeutic approach in cancer therapy
Targeting cholesterol metabolism in glioblastoma: a new therapeutic approach in cancer therapy
复制标题
DOI：
10.1136/jim-2018-000962
复制
发表时间：
2019-02
影响因子：
2.6
通讯作者：
L. Pirmoradi;N. Seyfizadeh;S. Ghavami;A. Zeki;S. Shojaei
中科院分区：
文献类型：
--
作者：
L. Pirmoradi;N. Seyfizadeh;S. Ghavami;A. Zeki;S. Shojaei
多形性胶质母细胞瘤（GBM）是已知的最具侵袭性的恶性脑肿瘤，尽管目前在癌症领域取得了进展，但其生存率很低。鉴于这种疾病的破坏性，迫切需要对GBM的病理生理学进行进一步研究。最近的研究表明，与健康的星形胶质细胞相比，GBM细胞具有独特的细胞生理学。有趣的是，GBM细胞不能通过甲羟戊酸途径重新合成胆固醇。因此，GBM细胞的存活依赖于低密度脂蛋白受体（ldlr）对胆固醇的摄取，低密度脂蛋白受体以载脂蛋白e -含脂蛋白和atp结合盒转运蛋白A1 （ABCA1）的形式将多余的胆固醇排出细胞。肝X受体通过改变LDLR和ABCA1的表达来调节神经元和健康星形胶质细胞内胆固醇水平，以响应胆固醇及其衍生物。在GBM细胞中，由于这种监视途径的失调，细胞内胆固醇积累。此外，细胞内胆固醇通过质膜脂筏中死亡受体5的积累和激活调节替莫唑胺诱导的胶质母细胞瘤细胞死亡。甲羟戊酸途径和自噬通量也从根本上与细胞健康和死亡相关。因此，通过胆固醇代谢，甲羟戊酸途径可能在GBM的发病机制和治疗中发挥关键作用，这是我们目前仍缺乏了解的。靶向胆固醇代谢的GBM可能有望作为一种新的辅助临床治疗这种毁灭性的癌症。
Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor known with a poor survival rate despite current advances in the field of cancer. Additional research into the pathophysiology of GBM is urgently needed given the devastating nature of this disease. Recent studies have revealed the unique cellular physiology of GBM cells as compared with healthy astrocytes. Intriguingly, GBM cells are incapable of de novo cholesterol synthesis via the mevalonate pathway. Thus, the survival of GBM cells depends on cholesterol uptake via low-density lipoprotein receptors (LDLRs) in the form of apolipoprotein-E-containing lipoproteins and ATP-binding cassette transporter A1 (ABCA1) that efflux surplus cholesterol out of cells. Liver X receptors regulate intracellular cholesterol levels in neurons and healthy astrocytes through changes in the expression of LDLR and ABCA1 in response to cholesterol and its derivatives. In GBM cells, due to the dysregulation of this surveillance pathway, there is an accumulation of intracellular cholesterol. Furthermore, intracellular cholesterol regulates temozolomide-induced cell death in glioblastoma cells via accumulation and activation of death receptor 5 in plasma membrane lipid rafts. The mevalonate pathway and autophagy flux are also fundamentally related with implications for cell health and death. Thus, via cholesterol metabolism, the mevalonate pathway may be a crucial player in the pathogenesis and treatment of GBM where our current understanding is still lacking. Targeting cholesterol metabolism in GBM may hold promise as a novel adjunctive clinical therapy for this devastating cancer.