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Inhibition of cancer cell proliferation by PPARγ is mediated by a metabolic switch that increases reactive oxygen species levels

机译:PPARγ对癌细胞增殖的抑制作用是由代谢开关介导的,该代谢开关增加了活性氧的水平

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摘要

The nuclear receptor peroxisome-proliferation-activated receptor gamma (PPARγ), a transcriptional master regulator of glucose and lipid metabolism, inhibits the growth of several common cancers, including lung cancer. In this study, we show that the mechanism by which activation of PPARγ inhibits proliferation of lung cancer cells is based on metabolic changes. We found that treatment with the PPARγ agonist pioglitazone triggers a metabolic switch that inhibits pyruvate oxidation and reduces glutathione levels. These PPARγ-induced metabolic changes result in a marked increase of reactive oxygen species (ROS) levels that lead to rapid hypophosphorylation of retinoblastoma protein (RB) and cell-cycle arrest. The antiproliferative effect of PPARγ activation can be prevented by suppressing pyruvate dehydrogenase kinase 4 (PDK4) or β-oxidation of fatty acids in vitro and in vivo. Our proposed mechanism also suggests that metabolic changes can rapidly and directly inhibit cell-cycle progression of cancer cells by altering ROS levels.
机译:核受体过氧化物酶体增殖激活受体γ(PPARγ)是葡萄糖和脂质代谢的转录主调节剂,可抑制几种常见癌症(包括肺癌)的生长。在这项研究中,我们表明激活PPARγ抑制肺癌细胞增殖的机制是基于代谢变化的。我们发现用PPARγ激动剂吡格列酮治疗可触发代谢转换,从而抑制丙酮酸氧化并降低谷胱甘肽水平。这些PPARγ诱导的代谢变化导致活性氧(ROS)水平显着增加,导致视网膜母细胞瘤蛋白(RB)迅速过磷酸化和细胞周期停滞。通过抑制丙酮酸脱氢酶激酶4(PDK4)或体外和体内脂肪酸的β-氧化,可以防止PPARγ激活的抗增殖作用。我们提出的机制还表明,通过改变ROS水平,代谢变化可以迅速,直接地抑制癌细胞的细胞周期进程。

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