The glucose dependence of Akt-transformed cells can be reversed by pharmacologic activation of fatty acid β-oxidation
The glucose dependence of Akt-transformed cells can be reversed by pharmacologic activation of fatty acid β-oxidation
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DOI：
10.1038/sj.onc.1208622
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发表时间：
2005-06-16
期刊：
影响因子：
8
通讯作者：
Thompson, CB
中科院分区：
文献类型：
--
作者：
Buzzai, M;Bauer, DE;Thompson, CB
致癌激酶Akt的激活刺激癌细胞摄取葡萄糖并进行代谢，且使这些细胞在葡萄糖缺失时易于死亡。在此我们表明，5 - 氨基咪唑 - 4 - 甲酰胺核糖核苷（AICAR）逆转了表达Akt的胶质母细胞瘤细胞对葡萄糖剥夺的敏感性。AICAR的保护作用依赖于AMPK的激活，因为AMPK的显性失活形式的表达消除了这种效应。AMPK是一种细胞能量传感器，其激活既能阻断诸如蛋白质合成等合成代谢途径，又能激活诸如脂肪酸氧化等分解代谢反应以维持细胞的生物能学。虽然雷帕霉素处理模拟了AICAR对抑制帽依赖翻译标志物的作用，但它未能保护表达Akt的细胞在葡萄糖缺失时免于死亡。与对照细胞相比，表达Akt的细胞在响应葡萄糖剥夺时诱导脂肪酸氧化的能力受损，除非用AICAR刺激。刺激脂肪酸氧化足以维持细胞存活，因为用苯扎贝特激活脂肪酸氧化也能保护表达Akt的细胞免受葡萄糖缺失诱导的死亡。相反，用肉碱棕榈酰转移酶 - 1（CPT - 1）抑制剂处理以阻断脂肪酸进入线粒体，可阻止AICAR在无葡萄糖时刺激脂肪酸氧化并促进细胞存活。最后，细胞存活不需要逆转Akt对蛋白质翻译或脂质合成的影响，因为添加细胞可渗透的可氧化底物丙酮酸甲酯足以维持缺乏葡萄糖的表达Akt的细胞的存活。总之，这些数据表明Akt的激活阻断了癌细胞代谢非糖酵解生物能底物的能力，导致对葡萄糖的依赖。
Activation of the oncogenic kinase Akt stimulates glucose uptake and metabolism in cancer cells and renders these cells susceptible to death in response to glucose withdrawal. Here we show that 5-aminoimidazole-4-carboxamide ribonucleoside ( AICAR) reverses the sensitivity of Akt-expressing glioblastoma cells to glucose deprivation. AICAR's protection depends on the activation of AMPK, as expression of a dominant-negative form of AMPK abolished this effect. AMPK is a cellular energy sensor whose activation can both block anabolic pathways such as protein synthesis and activate catabolic reactions such as fatty acid oxidation to maintain cellular bioenergetics. While rapamycin treatment mimicked the effect of AICAR on inhibiting markers of cap-dependent translation, it failed to protect Akt-expressing cells from death upon glucose withdrawal. Compared to control cells, Akt-expressing cells were impaired in the ability to induce fatty acid oxidation in response to glucose deprivation unless stimulated with AICAR. Stimulation of fatty acid oxidation was sufficient to maintain cell survival as activation of fatty acid oxidation with bezafibrate also protected Akt-expressing cells from glucose withdrawal-induced death. Conversely, treatment with a CPT-1 inhibitor to block fatty acid import into mitochondria prevented AICAR from stimulating fatty acid oxidation and promoting cell survival in the absence of glucose. Finally, cell survival did not require reversal of Akt's effects on either protein translation or lipid synthesis as the addition of the cell penetrant oxidizable substrate methyl-pyruvate was sufficient to maintain survival of Akt-expressing cells deprived of glucose. Together, these data suggest that activation of Akt blocks the ability of cancer cells to metabolize nonglycolytic bioenergetic substrates, leading to glucose addiction.