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首页> 外文期刊>Cell cycle >Low-dose arsenic-mediated metabolic shift is associated with activation of Polo-like kinase 1 (Plk1)
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Low-dose arsenic-mediated metabolic shift is associated with activation of Polo-like kinase 1 (Plk1)

机译：低剂量砷介导的代谢转变与Polo样激酶1（Plk1）的激活有关

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摘要

Arsenic is a well-established human carcinogen associated with cancers of the skin, liver, lung, kidney, and bladder. Although numerous carcinogenic pathways have been proposed, the molecular mechanisms underlying arsenic-associated cancer etiology are still elusive. The cellular responses to arsenic exposure are dose dependent. It was recently shown that low-dose arsenic leads to a metabolic shift from mitochondrial respiration to aerobic glycolysis via inactivation of tumor suppressor p53 and activation of NF-B. However, how inactivation of p53, activation of NF-B, and metabolic change are coordinated in response to low-dose arsenic exposure is still not completely understood. Polo-like kinase 1 (Plk1) is a well- documented regulator in many cell cycle-related events. Herein, we showed that low-dose arsenic leads to elevation of Plk1 in an NF-B-dependent manner and that elevation of Plk1 contributes to the metabolic change from oxidative phosphorylation to glycolysis via activation of the PI3K/AKT/mTOR pathway. Furthermore, we showed that inhibition/depletion of Plk1 reverses low-dose arsenic-associated phenotypes, including enhanced cell proliferation, activation of the PI3K/AKT/mTOR pathway, and increased glycolysis. Finally, inhibition of the PI3K/AKT/mTOR pathway also antagonizes the enhanced glycolytic influx due to low-dose arsenic exposure. Our studies support the notion that Plk1 likely plays a critical role in cellular responses to low-dose arsenic.
机译：砷是与皮肤，肝，肺，肾和膀胱癌相关的公认的人类致癌物。尽管已经提出了许多致癌途径，但是与砷相关的癌症病因的分子机制仍然难以捉摸。细胞对砷暴露的反应是剂量依赖性的。最近显示，低剂量的砷通过灭活肿瘤抑制因子p53和激活NF-B导致代谢从线粒体呼吸转变为有氧糖酵解。然而，仍未完全了解如何响应低剂量砷暴露来协调p53的失活，NF-B的激活和代谢变化。 Polo样激酶1（Plk1）在许多细胞周期相关事件中是有据可查的调节剂。在这里，我们表明，低剂量的砷导致NF-B依赖的方式导致Plk1升高，并且Plk1的升高通过PI3K / AKT / mTOR途径的激活，促进了从氧化磷酸化到糖酵解的代谢变化。此外，我们表明抑制/消耗Plk1可以逆转低剂量砷相关的表型，包括增强的细胞增殖，PI3K / AKT / mTOR途径的激活和糖酵解的增加。最后，由于低剂量砷暴露，对PI3K / AKT / mTOR途径的抑制作用也拮抗了增强的糖酵解作用。我们的研究支持以下观点：Plk1可能在细胞对低剂量砷的反应中起关键作用。

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