Department of Membrane Transport Biophysics, Institute of Physiology, vvi, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Int J Biochem Cell Biol. 2011 Jul;43(7):950-68. doi: 10.1016/j.biocel.2010.05.003. Epub 2010 May 10.
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 HIFα prolines.
无论恶性肿瘤是由基因表达的基本重编程引发的，还是由干细胞引发的，在致癌过程中都会发生促进代谢变化的“基因表达波”，这些变化始于癌基因介导的变化，随后是缺氧诱导因子（HIF）介导的基因表达，这两者都导致高度糖酵解的“Warburg”表型和线粒体生物发生的抑制。由于恶性肿瘤中的高增殖率导致低糖血症和营养缺乏，第三波（第二次癌基因）适应刺激谷氨酰胺分解，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 轴和 MYC 失调。氧化谷氨酰胺分解作为一种替代途径，可补偿细胞内的 ATP。与缺氧谷氨酰胺分解一起，它提供丙酮酸、乳酸和 NADPH 池（替代戊糖磷酸途径）。来自恢复活力的线粒体的逆行信号可能构成基因重编程的第四波。反过来，当两个三羧酸循环酶逆转时，谷氨酰胺分解在缺氧时甚至可能部分（暂时）起作用，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。我们讨论了致癌基因的生物能量相关功能、线粒体生物发生/降解在致癌作用中的参与、尚未解释的即时葡萄糖阻断呼吸的 Crabtree 效应，以及源于琥珀酸、富马酸、丙酮酸、乳酸和草酰乙酸积累的代谢信号通过干扰脯氨酰羟化酶结构域酶介导的 HIFα脯氨酸的羟化。
