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首页> 外文期刊>Cancer research: The official organ of the American Association for Cancer Research, Inc >Inhibition of AMPK and krebs cycle gene expression drives metabolic remodeling of Pten-deficient preneoplastic thyroid cells
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Inhibition of AMPK and krebs cycle gene expression drives metabolic remodeling of Pten-deficient preneoplastic thyroid cells

机译:抑制AMPK和krebs周期基因表达可驱动Pten缺陷型肿瘤前甲状腺细胞的代谢重塑

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摘要

Rapidly proliferating and neoplastically transformed cells generate the energy required to support rapid cell division by increasing glycolysis and decreasing flux through the oxidative phosphorylation (OXPHOS) pathway, usually without alterations in mitochondrial function. In contrast, little is known of the metabolic alterations, if any, which occur in cells harboring mutations that prime their neoplastic transformation. To address this question, we used a Pten-deficient mouse model to examine thyroid cells where a mild hyperplasia progresses slowly to follicular thyroid carcinoma. Using this model, we report that constitutive phosphoinositide 3-kinase (PI3K) activation caused by PTEN deficiency in nontransformed thyrocytes results in a global downregulation of Krebs cycle and OXPHOS gene expression, defective mitochondria, reduced respiration, and an enhancement in compensatory glycolysis. We found that this process does not involve any of the pathways classically associated with the Warburg effect. Moreover, this process was independent of proliferation but contributed directly to thyroid hyperplasia. Our findings define a novel metabolic switch to glycolysis driven by PI3K-dependent AMPK inactivation with a consequent repression in the expression of key metabolic transcription regulators.
机译:快速增殖和赘生性转化的细胞通过增加糖酵解和通过氧化磷酸化(OXPHOS)途径减少通量来产生支持快速细胞分裂所需的能量,通常不会改变线粒体功能。相反,鲜为人知的是在具有引发其赘生性转化的突变的细胞中发生的代谢变化(如果有的话)。为了解决这个问题,我们使用Pten缺陷型小鼠模型检查了甲状腺细胞,其中轻度增生缓慢发展为滤泡性甲状腺癌。使用此模型,我们报告由非转化的甲状腺细胞中PTEN缺乏引起的组成型磷酸肌醇3激酶(PI3K)激活导致Krebs周期和OXPHOS基因表达的全局下调,线粒体缺陷,呼吸作用降低以及代偿性糖酵解增强。我们发现,此过程不涉及与Warburg效应经典相关的任何途径。此外,该过程与增殖无关,但直接促成甲状腺增生。我们的发现定义了由PI3K依赖的AMPK失活驱动的糖代谢的新的代谢转换,从而抑制了关键代谢转录调节因子的表达。

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