Fenofibrate Induces Ketone Body Production in Melanoma and Glioblastoma Cells.
Fenofibrate Induces Ketone Body Production in Melanoma and Glioblastoma Cells.
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DOI：
10.3389/fendo.2016.00005
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发表时间：
2016
影响因子：
5.2
通讯作者：
Reiss K
中科院分区：
文献类型：
--
作者：
Grabacka MM;Wilk A;Antonczyk A;Banks P;Walczyk-Tytko E;Dean M;Pierzchalska M;Reiss K
酮体[β-羟基丁酸（bHB）和乙酰乙酸]主要在长期禁食或饥饿期间在肝脏中产生。 bHB 是一种非常有效的能量底物，可维持外周组织中 ATP 的产生；重要的是，它的消耗优于葡萄糖。然而，大多数恶性细胞，特别是神经外胚层来源的癌细胞，例如胶质母细胞瘤，不能使用酮体作为能量来源。在此，我们报告了一项新的观察结果，即非诺贝特（一种合成的过氧化物酶体增殖物激活受体 α (PPARa) 激动剂）可诱导黑色素瘤和胶质母细胞瘤细胞以及由非转化细胞组成的神经球中产生 bHB。出乎意料的是，这种作用并不依赖于 PPARa 活性或其表达水平。非诺贝特诱导的生酮伴随着生长停滞和转酮醇酶下调，但 NADP/NADPH 和 GSH/GSSG 比率不受影响。我们的结果揭示了癌细胞生物学的一个新的、有趣的方面，并强调了非诺贝特作为针对胶质母细胞瘤的经典和饮食（生酮）治疗方法的补充的益处。
Ketone bodies [beta-hydroxybutyrate (bHB) and acetoacetate] are mainly produced in the liver during prolonged fasting or starvation. bHB is a very efficient energy substrate for sustaining ATP production in peripheral tissues; importantly, its consumption is preferred over glucose. However, the majority of malignant cells, particularly cancer cells of neuroectodermal origin such as glioblastoma, are not able to use ketone bodies as a source of energy. Here, we report a novel observation that fenofibrate, a synthetic peroxisome proliferator-activated receptor alpha (PPARa) agonist, induces bHB production in melanoma and glioblastoma cells, as well as in neurospheres composed of non-transformed cells. Unexpectedly, this effect is not dependent on PPARa activity or its expression level. The fenofibrate-induced ketogenesis is accompanied by growth arrest and downregulation of transketolase, but the NADP/NADPH and GSH/GSSG ratios remain unaffected. Our results reveal a new, intriguing aspect of cancer cell biology and highlight the benefits of fenofibrate as a supplement to both canonical and dietary (ketogenic) therapeutic approaches against glioblastoma.