Hypo- and hyperactivated Notch signaling induce a glycolytic switch through distinct mechanisms
Hypo- and hyperactivated Notch signaling induce a glycolytic switch through distinct mechanisms
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DOI：
10.1073/pnas.1104943108
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发表时间：
2011-11-15
影响因子：
11.1
通讯作者：
Sahlgren, Cecilia Maria
中科院分区：
文献类型：
--
作者：
Landor, Sebastian K. -J.;Mutvei, Anders P.;Sahlgren, Cecilia Maria
在癌细胞中经常观察到从氧化磷酸化到糖酵解的转换，并且与肿瘤生长和侵袭有关，但控制转换的基础分子机制知之甚少。在这份报告中，我们表明Notch信号是细胞代谢的关键调节因子。高活化和低活化的Notch均诱导乳腺肿瘤细胞中的糖酵解表型，尽管通过不同的机制：高活化的Notch信号传导通过激活磷脂酰肌醇3-激酶/AKT丝氨酸/苏氨酸激酶途径导致糖酵解增加，而低活化的Notch信号传导减弱线粒体活性并以p53依赖性方式诱导糖酵解。尽管具有高活化和低活化Notch信号传导的细胞显示出增强的糖酵解，但在异种移植小鼠模型中，仅具有高活化Notch的细胞促进侵袭性肿瘤生长。这种现象可以解释为，只有Notch过度活化，但不是低活化，细胞保留的能力，切换回氧化磷酸化。总之，我们的数据揭示了Notch在细胞能量稳态中的作用，并表明Notch信号传导是代谢灵活性所必需的。
A switch from oxidative phosphorylation to glycolysis is frequently observed in cancer cells and is linked to tumor growth and invasion, but the underpinning molecular mechanisms controlling the switch are poorly understood. In this report we show that Notch signaling is a key regulator of cellular metabolism. Both hyper- and hypoactivated Notch induce a glycolytic phenotype in breast tumor cells, although by distinct mechanisms: hyperactivated Notch signaling leads to increased glycolysis through activation of the phosphatidylinositol 3-kinase/AKT serine/threonine kinase pathway, whereas hypoactivated Notch signaling attenuates mitochondrial activity and induces glycolysis in a p53-dependent manner. Despite the fact that cells with both hyper- and hypoactivated Notch signaling showed enhanced glycolysis, only cells with hyperactivated Notch promoted aggressive tumor growth in a xenograft mouse model. This phenomenon may be explained by that only Notch-hyperactivated, but not -hypoactivated, cells retained the capacity to switch back to oxidative phosphorylation. In conclusion, our data reveal a role for Notch in cellular energy homeostasis, and show that Notch signaling is required for metabolic flexibility.