PDF(Pubmed)
Abstract：
Hypoxia-inducible factor-1α (HIF1α) attenuates mitochondrial activity while promoting glycolysis. However, lower glycolysis is compromised in human clear cell renal cell carcinomas, in which HIF1α acts as a tumor suppressor by inhibiting cell-autonomous proliferation. Here, we find that, unexpectedly, HIF1α suppresses lower glycolysis after the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) step, leading to reduced lactate secretion in different tumor cell types when cells encounter a limited pyruvate supply such as that typically found in the tumor microenvironment in vivo. This is because HIF1α-dependent attenuation of mitochondrial oxygen consumption increases the NADH/NAD+ ratio that suppresses the activity of the NADH-sensitive GAPDH glycolytic enzyme. This is manifested when pyruvate supply is limited, since pyruvate acts as an electron acceptor that prevents the increment of the NADH/NAD+ ratio. Furthermore, this anti-glycolytic function provides a molecular basis to explain how HIF1α can suppress tumor cell proliferation by increasing the NADH/NAD+ ratio.
摘要：
缺氧诱导因子-1α（HIF1α）减弱线粒体活性，同时促进糖酵解。然而,较低的糖酵解在人类透明细胞肾细胞癌中受损，其中HIF1α通过抑制细胞自主增殖而充当肿瘤抑制剂。这里,我们发现,出乎意料的是,HIF1α抑制甘油醛3-磷酸脱氢酶（GAPDH）步骤后较低的糖酵解，当细胞遇到有限的丙酮酸供应时，例如通常在体内肿瘤微环境中发现的丙酮酸供应，导致不同肿瘤细胞类型中乳酸分泌减少。这是因为线粒体氧消耗的HIF1α依赖性衰减增加了抑制NADH敏感性GAPDH糖酵解酶活性的NADH/NAD比率。这表现在丙酮酸盐供应有限时，因为丙酮酸盐充当电子受体,防止NADH/NAD+比率的增加。此外，这种抗糖酵解功能为解释HIF1α如何通过增加NADH/NAD比率来抑制肿瘤细胞增殖提供了分子基础。
