The Warburg Effect Is Genetically Determined in Inherited Pheochromocytomas
The Warburg Effect Is Genetically Determined in Inherited Pheochromocytomas
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DOI：
10.1371/journal.pone.0007094
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发表时间：
2009-09-18
期刊：
影响因子：
3.7
通讯作者：
Gimenez-Roqueplo, Anne-Paule
中科院分区：
文献类型：
--
作者：
Favier, Judith;Briere, Jean-Jacques;Gimenez-Roqueplo, Anne-Paule
瓦尔堡效应描述了癌细胞如何下调其有氧呼吸并优先使用糖酵解来产生能量。为了评估缺氧和瓦尔堡效应之间的联系，我们研究了VHL、RET、NF 1和SDH基因种系突变诱导的嗜铬细胞瘤中线粒体电子传递、血管生成和糖酵解。SDH和VHL基因突变已被证明导致缺氧反应的激活，即使在常氧条件下，现在称为假缺氧的过程。我们观察到电子传递蛋白的表达和活性降低，与SDH和VHL相关的假缺氧肿瘤中血管生成增加相关，而糖酵解的刺激仅在VHL肿瘤中观察到。此外，微阵列分析表明，参与这些代谢途径的基因的表达是一个有效的工具，根据易感基因突变的嗜铬细胞瘤的分类。我们的数据提示假性缺氧和p53缺失之间存在意想不到的联系，这导致VHL相关嗜铬细胞瘤中明显的瓦尔堡效应。
The Warburg effect describes how cancer cells down-regulate their aerobic respiration and preferentially use glycolysis to generate energy. To evaluate the link between hypoxia and Warburg effect, we studied mitochondrial electron transport, angiogenesis and glycolysis in pheochromocytomas induced by germ-line mutations in VHL, RET, NF1 and SDH genes. SDH and VHL gene mutations have been shown to lead to the activation of hypoxic response, even in normoxic conditions, a process now referred to as pseudohypoxia. We observed a decrease in electron transport protein expression and activity, associated with increased angiogenesis in SDH- and VHL-related, pseudohypoxic tumors, while stimulation of glycolysis was solely observed in VHL tumors. Moreover, microarray analyses revealed that expression of genes involved in these metabolic pathways is an efficient tool for classification of pheochromocytomas in accordance with the predisposition gene mutated. Our data suggest an unexpected association between pseudohypoxia and loss of p53, which leads to a distinct Warburg effect in VHL-related pheochromocytomas.