Waves of gene regulation suppress and then restore oxidative phosphorylation in cancer cells
Waves of gene regulation suppress and then restore oxidative phosphorylation in cancer cells
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DOI：
10.1016/j.biocel.2010.05.003
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发表时间：
2011-07-01
影响因子：
4
通讯作者：
Jezek, Petr
中科院分区：
文献类型：
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作者：
Smolkova, Katarina;Plecita-Hlavata, Lydie;Jezek, Petr
我们假设以下假设：无论恶性肿瘤是由基因表达的根本性重新编程启动的，还是由干细胞播种的，促进代谢变化的基因表达“波”在癌变过程中发生，首先是癌基因介导的变化，然后是缺氧诱导因子(HIF)介导的基因表达，两者都导致高度糖酵解的“Warburg”表型和线粒体生物合成的抑制。由于恶性肿瘤的高增殖率导致血糖升高和营养缺乏，适应的第三波(第二癌基因)刺激谷氨酰胺分解，在某些情况下部分重新建立氧化磷酸化；这涉及LKB1-AMPK-P53。PI3K-Akt-mTOR轴与MYC失调。氧化谷氨酰胺分解是细胞内ATP代偿的另一种途径。与缺氧性谷氨酰胺分解一起，它提供丙酮酸、乳酸和NADPH池(替代戊糖磷酸途径)。恢复活力的线粒体发出的逆行信号可能构成了基因重新编程的第四波。反过来，当两种克雷布斯循环酶逆转时，谷氨酰胺分解可能部分(瞬时)发挥作用，甚至在缺氧期间，从而进一步促进恶性肿瘤。每个恶性肿瘤内致癌过程的历史决定了选定存活细胞的最终代谢表型，导致不同的癌症生物能量表型，从高度糖酵解的“经典Warburg”到部分或增强的氧化磷酸化。我们讨论了癌基因的生物能量相关功能，线粒体生物发生/降解在癌症发生中的参与，尚未解释的Crabtree效应，瞬时葡萄糖阻断呼吸，以及通过干扰Pro-羟基羟基酶结构域酶介导的HIFα-Pro的羟化，由琥珀酸、富马酸、丙酮酸、乳酸和羟戊二酸积累产生的代谢信号。(C)2010爱思唯尔有限公司。保留所有权利。
We posit the following hypothesis: Independently of whether malignant tumors are initiated by a fundamental reprogramming of gene expression or seeded by stem cells, "waves" of gene expression that promote metabolic changes occur during carcinogenesis, beginning with oncogene-mediated changes, followed by hypoxia-induced factor (HIF)-mediated gene expression, both resulting in the highly glycolytic "Warburg" phenotype and suppression of mitochondrial biogenesis. Because high proliferation rates in malignancies cause aglycemia and nutrient shortage, the third (second oncogene) "wave" of adaptation stimulates glutaminolysis, which in certain cases partially re-establishes oxidative phosphorylation; this involves the LKB1-AMPK-p53. PI3K-Akt-mTOR axes and MYC dysregulation. Oxidative glutaminolysis serves as an alternative pathway compensating for cellular ATP. Together with anoxic glutaminolysis it provides pyruvate, lactate, and the NADPH pool (alternatively to pentose phosphate pathway). Retrograde signaling from revitalized mitochondria might constitute the fourth "wave" of gene reprogramming. In turn, upon reversal of the two Krebs cycle enzymes, glutaminolysis may partially (transiently) function even during anoxia, thereby further promoting malignancy. The history of the carcinogenic process within each malignant tumor determines the final metabolic phenotype of the selected surviving cells, resulting in distinct cancer bioenergetic phenotypes ranging from the highly glycolytic "classic Warburg" to partial or enhanced oxidative phosphorylation. We discuss the bioenergetically relevant functions of oncogenes, the involvement of mitochondrial biogenesis/degradation in carcinogenesis, the yet unexplained Crabtree effect of instant glucose blockade of respiration, and metabolic signaling stemming from the accumulation of succinate, fumarate, pyruvate, lactate, and oxoglutarate by interfering with prolyl hydroxylase domain enzyme-mediated hydroxylation of HIF alpha prolines. (C) 2010 Elsevier Ltd. All rights reserved.