Esumi Hiroyasu, Izuishi Kunihiko, Kato Kazuyoshi, Hashimoto Koichi, Kurashima Yukiko, Kishimoto Atsuhiro, Ogura Tsutomu, Ozawa Takayuki
Investigative Treatment Division, National Cancer Center Research Institute East 6-5-1, Kashiwanoha, Kashiwa, Chiba, Japan.
J Biol Chem. 2002 Sep 6;277(36):32791-8. doi: 10.1074/jbc.M112270200. Epub 2002 Jun 28.
Hypoxia is a critical event for higher organisms, and cells and tissues react by increasing the oxygen supply by vasodilatation, angiogenesis, and erythropoiesis and maintaining cellular energy by increasing glycolysis and inhibiting anabolic pathways. Stimulation of glycolysis has been regarded as the main response that increases energy production during hypoxia; however, there is an obvious conflict during ischemia, because both the oxygen and glucose supply are insufficient. In this study, we found that exposure of HepG2 cells and normal fibroblasts to hypoxia induces cellular tolerance to glucose starvation. The tolerance induced by hypoxia is dependent on several amino acids, indicating a switch from glucose to amino acids as the energy source. When antisense RNA expression vector for 5'-AMP-activated protein kinase or protein kinase B/Akt was transfected into HepG2 cells, the induction of tolerance to glucose was greatly inhibited, indicating that the tolerance was dependent on 5'-AMP-activated protein kinase and protein kinase B/Akt. Similar tolerance was induced by nitric oxide exposure. The tolerance induced was observed in various cells and may represent a previously unknown physiological response related to hypoxia-preconditioning and tumor progression:austerity.
缺氧对高等生物而言是一个关键事件，细胞和组织会通过血管舒张、血管生成和红细胞生成来增加氧气供应，并通过增加糖酵解和抑制合成代谢途径来维持细胞能量。糖酵解的刺激被认为是缺氧期间增加能量产生的主要反应；然而，在缺血期间存在明显矛盾，因为氧气和葡萄糖供应均不足。在本研究中，我们发现将HepG2细胞和正常成纤维细胞暴露于缺氧环境会诱导细胞对葡萄糖饥饿产生耐受性。缺氧诱导的耐受性依赖于几种氨基酸，这表明能量来源从葡萄糖转变为氨基酸。当将针对5'-AMP激活蛋白激酶或蛋白激酶B/Akt的反义RNA表达载体转染到HepG2细胞中时，对葡萄糖耐受性的诱导受到极大抑制，这表明该耐受性依赖于5'-AMP激活蛋白激酶和蛋白激酶B/Akt。一氧化氮暴露也可诱导类似的耐受性。在各种细胞中均观察到诱导的耐受性，这可能代表一种与缺氧预处理和肿瘤进展相关的先前未知的生理反应：节俭。
