Cancer Research UK, The Beatson Institute for Cancer Research, Glasgow, UK.
J Mol Med (Berl). 2011 Mar;89(3):213-20. doi: 10.1007/s00109-011-0728-4. Epub 2011 Feb 8.
The observation that altered metabolism is the fundamental cause of cancer was made by Otto Warburg nearly a century ago. However, the subsequent identification of oncogenes and tumor suppressor genes has displaced Warburg's theory pointing towards genetic aberrations as the underlining cause of cancer. Nevertheless, in the last decade, cancer-associated mutations have been identified in genes coding for tricarboxylic acid cycle (TCA cycle, also known as Krebs cycle) and closely related enzymes that have essential roles in cellular metabolism. These observations have revived interest in Warburg's hypothesis and prompted a flurry of functional studies in the hope of gaining mechanistic insight into the links between mitochondrial dysfunction, metabolic alterations, and cancer. In this review, we discuss the potential pro-oncogenic signaling role of some TCA cycle metabolites and their derivatives (oncometabolites). In particular, we focus on their effects on dioxygenases, a family of oxygen and α-ketoglutarate-dependent enzymes that control, among other things, the levels and activity of the hypoxia-inducible transcription factors and the activity of DNA and histone demethylases.
近一个世纪前，奥托·瓦伯格（Otto Warburg）就已经观察到代谢改变是癌症的根本原因。然而，随后鉴定的癌基因和肿瘤抑制基因已将瓦伯格的理论取而代之，指出基因异常是癌症的根本原因。尽管如此，在过去十年中，已经在编码三羧酸循环（TCA 循环，也称为克雷布斯循环）及其密切相关酶的基因中鉴定出与癌症相关的突变，这些基因在细胞代谢中起着至关重要的作用。这些观察结果重新激发了人们对瓦伯格假说的兴趣，并促使人们进行了大量的功能研究，希望深入了解线粒体功能障碍、代谢改变与癌症之间的联系。在这篇综述中，我们讨论了一些 TCA 循环代谢物及其衍生物（致癌代谢物）的潜在致癌信号作用。特别是，我们重点介绍了它们对双加氧酶的影响，双加氧酶是一类依赖氧气和α-酮戊二酸的酶，除其他外，它们可以控制缺氧诱导转录因子的水平和活性以及 DNA 和组蛋白去甲基化酶的活性。
