Nuclear receptors and the Warburg effect in cancer.
Nuclear receptors and the Warburg effect in cancer.
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DOI：
10.1002/ijc.29012
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发表时间：
2015-10-01
影响因子：
6.4
通讯作者：
Campbell MJ
中科院分区：
文献类型：
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作者：
Thorne JL;Campbell MJ
1927年奥托·沃伯格证实肿瘤的能量主要来源于葡萄糖转化为乳酸，只有部分来源于细胞呼吸作用。在20世纪50年代，他提出，所有癌症的原因都反映了不同的机制，使细胞呼吸功能丧失，有利于发酵（现在称为有氧糖酵解）。异常葡萄糖代谢在癌症中的作用现在已经得到了明确的证实。从氧化磷酸化到代谢昂贵的有氧糖酵解的转变有点违反直觉，因为它的浪费性质。维持细胞效率有多个控制过程，这些机制很可能被破坏，以促进向依赖有氧糖酵解的转变。一个这样的细胞控制过程是由核受体超家族介导的。这个转录因子大家庭在感知环境信号和控制增殖、分化和细胞死亡的决定方面发挥着重要作用，例如，调节葡萄糖摄取和代谢，调节致癌基因和肿瘤抑制因子的作用。在这篇综述中，我们强调了在致瘤转化过程中核受体的作用被改变的机制，并可以促进向有氧糖酵解的转变。在最简单的层面上，NR行为的基本改变可以增强糖酵解通量，从而为提高肿瘤微环境中的生存提供基础。在这种情况下，改善增强的NR活性可能有助于癌细胞对华宝靶向治疗的敏感性，并可能提供未来的药物靶点。
In 1927 Otto Warburg established that tumours derive energy primarily from the conversion of glucose to lactic acid and only partially through cellular respiration involving oxygen. In the 1950s he proposed that all causes of cancer reflected different mechanisms of disabling cellular respiration in favour of fermentation (now termed aerobic glycolysis). The role of aberrant glucose metabolism in cancer is now firmly established. The shift away from oxidative phosphorylation towards the metabolically expensive aerobic glycolysis is somewhat counter-intuitive given its wasteful nature. Multiple control processes are in place to maintain cellular efficiency and it is likely that these mechanisms are disrupted to facilitate the shift to the reliance on aerobic glycolysis. One such process of cell control is mediated by the nuclear receptor superfamily. This large family of transcription factors plays a significant role in sensing environmental cues and controlling decisions on proliferation, differentiation and cell death for example, to regulate glucose uptake and metabolism and to modulate the actions of oncogenes and tumour suppressors. In this review we highlight mechanisms by which nuclear receptors actions are altered during tumorigenic transformation and can serve to enhance the shift to aerobic glycolysis. At the simplest level, a basic alteration in NR behaviour can serve to enhance glycolytic flux thus providing a basis for enhanced survival within the tumour micro-environment. Ameliorating the enhanced NR activity in this context may help to sensitize cancer cells to Warburg targeted therapies and may provide future drug targets.