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首页> 外文期刊>Molecular and Cellular Biology >Molecular Mechanisms of Fenofibrate-Induced Metabolic Catastrophe and Glioblastoma Cell Death
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Molecular Mechanisms of Fenofibrate-Induced Metabolic Catastrophe and Glioblastoma Cell Death

机译：非诺贝特诱导的代谢突变和胶质母细胞瘤细胞死亡的分子机制

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Fenofibrate (FF) is a common lipid-lowering drug and a potent agonist of the peroxisome proliferator-activated receptor alpha (PPARα). FF and several other agonists of PPARα have interesting anticancer properties, and our recent studies demonstrate that FF is very effective against tumor cells of neuroectodermal origin. In spite of these promising anticancer effects, the molecular mechanism(s) of FF-induced tumor cell toxicity remains to be elucidated. Here we report a novel PPARα-independent mechanism explaining FF's cytotoxicity in vitro and in an intracranial mouse model of glioblastoma. The mechanism involves accumulation of FF in the mitochondrial fraction, followed by immediate impairment of mitochondrial respiration at the level of complex I of the electron transport chain. This mitochondrial action sensitizes tested glioblastoma cells to the PPARα-dependent metabolic switch from glycolysis to fatty acid β-oxidation. As a consequence, prolonged exposure to FF depletes intracellular ATP, activates the AMP-activated protein kinase–mammalian target of rapamycin–autophagy pathway, and results in extensive tumor cell death. Interestingly, autophagy activators attenuate and autophagy inhibitors enhance FF-induced glioblastoma cytotoxicity. Our results explain the molecular basis of FF-induced glioblastoma cytotoxicity and reveal a new supplemental therapeutic approach in which intracranial infusion of FF could selectively trigger metabolic catastrophe in glioblastoma cells.
机译：非诺贝特（FF）是一种常见的降脂药物，并且是过氧化物酶体增殖物激活受体α（PPARα）的有效激动剂。 FF和其他几种PPARα激动剂具有有趣的抗癌特性，我们的最新研究表明FF对神经外胚层起源的肿瘤细胞非常有效。尽管有这些有希望的抗癌作用，但FF诱导的肿瘤细胞毒性的分子机制仍有待阐明。在这里，我们报告了一种新颖的PPARα独立机制，可解释FF在体外和在成胶质母细胞瘤的颅内小鼠模型中的细胞毒性。该机理涉及FF在线粒体部分中的积累，然后在电子传输链的复合物I水平上立即损害线粒体呼吸。这种线粒体作用使受试胶质母细胞瘤细胞对从糖酵解到脂肪酸β-氧化的PPARα依赖性代谢转换敏感。结果，长时间暴露于FF会耗尽细胞内ATP，激活AMP激活的蛋白激酶-雷帕霉素的哺乳动物靶标-自噬途径，并导致广泛的肿瘤细胞死亡。有趣的是，自噬激活剂减弱并且自噬抑制剂增强了FF诱导的胶质母细胞瘤的细胞毒性。我们的结果解释了FF诱导的胶质母细胞瘤细胞毒性的分子基础，并揭示了一种新的辅助治疗方法，其中颅内注入FF可以选择性地触发胶质母细胞瘤细胞的代谢灾难。

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