Institute of Developmental Biology and Cancer Research, CNRS-UMR 6543, Centre Antoine Lacassagne, University of Nice-Sophia Antipolis Nice, France.
Front Oncol. 2012 Feb 28;2:18. doi: 10.3389/fonc.2012.00018. eCollection 2012.
The hypoxia-inducible factor 1 (HIF-1), in addition to genetic and epigenetic changes, is largely responsible for alterations in cell metabolism in hypoxic tumor cells. This transcription factor not only favors cell proliferation through the metabolic shift from oxidative phosphorylation to glycolysis and lactic acid production but also stimulates nutrient supply by mediating adaptive survival mechanisms. In this study we showed that glycogen synthesis is enhanced in non-cancer and cancer cells when exposed to hypoxia, resulting in a large increase in glycogen stores. Furthermore, we demonstrated that the mRNA and protein levels of the first enzyme of glycogenesis, phosphoglucomutase1 (PGM1), were increased in hypoxia. We showed that induction of glycogen storage as well as PGM1 expression were dependent on HIF-1 and HIF-2. We established that hypoxia-induced glycogen stores are rapidly mobilized in cells that are starved of glucose. Glycogenolysis allows these "hypoxia-preconditioned" cells to confront and survive glucose deprivation. In contrast normoxic control cells exhibit a high rate of cell death following glucose removal. These findings point to the important role of hypoxia and HIF in inducing mechanisms of rapid adaptation and survival in response to a decrease in oxygen tension. We propose that a decrease in pO(2) acts as an "alarm" that prepares the cells to face subsequent nutrient depletion and to survive.
缺氧诱导因子 1（HIF-1）除了遗传和表观遗传变化外，在很大程度上负责改变缺氧肿瘤细胞的细胞代谢。这种转录因子不仅通过从氧化磷酸化到糖酵解和乳酸生成的代谢转变促进细胞增殖，而且还通过调节适应性生存机制来刺激营养供应。在这项研究中，我们表明，当非癌细胞和癌细胞暴露于缺氧时，糖原合成增强，导致糖原储存大量增加。此外，我们证明了糖异生的第一酶磷酸葡萄糖变位酶 1（PGM1）的 mRNA 和蛋白水平在缺氧时增加。我们表明，糖原储存的诱导以及 PGM1 表达依赖于 HIF-1 和 HIF-2。我们建立了缺氧诱导的糖原储存可以在缺乏葡萄糖的细胞中迅速动员。糖酵解使这些“缺氧预处理”细胞能够应对并在葡萄糖缺乏时存活。相比之下，正常氧对照细胞在葡萄糖去除后表现出高的细胞死亡率。这些发现表明缺氧和 HIF 在诱导快速适应和生存机制方面起着重要作用，以应对氧张力的降低。我们提出，pO2 的降低充当“警报”，使细胞为随后的营养耗竭做好准备并存活。
