Laboratory of Cancer Cell Biology, Graduate School of Biostudies, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan.
Int J Mol Sci. 2019 Jan 9;20(2):238. doi: 10.3390/ijms20020238.
Normal cells produce adenosine 5'-triphosphate (ATP) mainly through mitochondrial oxidative phosphorylation (OXPHOS) when oxygen is available. Most cancer cells, on the other hand, are known to produce energy predominantly through accelerated glycolysis, followed by lactic acid fermentation even under normoxic conditions. This metabolic phenomenon, known as aerobic glycolysis or the Warburg effect, is less efficient compared with OXPHOS, from the viewpoint of the amount of ATP produced from one molecule of glucose. However, it and its accompanying pathway, the pentose phosphate pathway (PPP), have been reported to provide advantages for cancer cells by producing various metabolites essential for proliferation, malignant progression, and chemo/radioresistance. Here, focusing on a master transcriptional regulator of adaptive responses to hypoxia, the hypoxia-inducible factor 1 (HIF-1), we review the accumulated knowledge on the molecular basis and functions of the Warburg effect and its accompanying pathways. In addition, we summarize our own findings revealing that a novel HIF-1-activating factor enhances the antioxidant capacity and resultant radioresistance of cancer cells though reprogramming of the glucose metabolic pathway.
正常细胞在有氧气的情况下主要通过线粒体氧化磷酸化（OXPHOS）产生腺嘌呤核苷 5'-三磷酸（ATP）。另一方面，大多数癌细胞已知主要通过加速糖酵解产生能量，即使在常氧条件下也是如此，随后进行乳酸发酵。从一个葡萄糖分子产生的 ATP 量来看，这种代谢现象，称为有氧糖酵解或瓦堡效应，与 OXPHOS 相比效率较低。然而，它及其伴随的途径，磷酸戊糖途径（PPP），通过产生各种对于增殖、恶性进展和化疗/放射抵抗至关重要的代谢物，为癌细胞提供了优势。在这里，我们重点关注缺氧适应反应的主要转录调节因子，缺氧诱导因子 1（HIF-1），综述了瓦堡效应及其伴随途径的分子基础和功能的已有知识。此外，我们总结了我们自己的发现，揭示了一种新型的 HIF-1 激活因子通过重编程葡萄糖代谢途径增强了癌细胞的抗氧化能力和由此产生的放射抗性。
