P53 regulates glucose metabolism through an IKK-NF-κB pathway and inhibits cell transformation
P53 regulates glucose metabolism through an IKK-NF-κB pathway and inhibits cell transformation
复制标题
DOI：
10.1038/ncb1724
复制
发表时间：
2008-05-01
影响因子：
21.3
通讯作者：
Tanaka, Nobuyuki
中科院分区：
文献类型：
--
作者：
Kawauchi, Keiko;Araki, Keigo;Tanaka, Nobuyuki
癌细胞优先使用有氧糖酵解来提供能量（1，2），这种代谢变化对肿瘤生长很重要（3，4）。在这里，我们发现了肿瘤抑制因子p53，转录因子NF-κ B和糖酵解之间的联系。在p53缺陷的原代培养细胞中，IKK α和IKK β的激酶活性以及随后的NF-κ B活性增强。NF-κ B B的活化，通过p53的缺失，引起有氧糖酵解速率的增加和Glu 3的上调。在p53缺陷细胞中，致癌Ras诱导的细胞转化和有氧糖酵解的加速在p65/NF-κ B表达缺失的情况下被抑制，并且通过GLUT 3表达恢复。研究还表明，糖酵解抑制剂减弱了p53缺陷细胞中增强的IKK活性。此外，在Ras表达p53缺陷细胞中，IKK活性被p65缺陷抑制，并通过GLUT 3表达恢复。总之，这些数据表明p53通过抑制糖酵解限制IKK-NF-κ B途径的激活。这些结果表明存在一个正反馈环，糖酵解驱动IKK-NF-κ B激活，p53缺失导致的该环的过度激活在癌基因诱导的细胞转化中是重要的。
Cancer cells use aerobic glycolysis preferentially for energy provision(1,2) and this metabolic change is important for tumour growth(3,4). Here, we have found a link between the tumour suppressor p53, the transcription factor NF-kappa B and glycolysis. In p53-deficient primary cultured cells, kinase activities of IKK alpha and IKK beta and subsequent NF-kappa B activity were enhanced. Activation of NF-kappa B, by loss of p53, caused an increase in the rate of aerobic glycolysis and upregulation of Glut3. Oncogenic Ras-induced cell transformation and acceleration of aerobic glycolysis in p53-deficient cells were suppressed in the absence of p65/ NF-kappa B expression, and were restored by GLUT3 expression. It was also shown that a glycolytic inhibitor diminished the enhanced IKK activity in p53-deficient cells. Moreover, in Ras-expressing p53-deficient cells, IKK activity was suppressed by p65 deficiency and restored by GLUT3 expression. Taken together, these data indicate that p53 restricts activation of the IKK - NF-kappa B pathway through suppression of glycolysis. These results suggest that a positivefeedback loop exists, whereby glycolysis drives IKK - NF-kappa B activation, and that hyperactivation of this loop by loss of p53 is important in oncogene- induced cell transformation.