CDK8 Kinase Activity Promotes Glycolysis.
CDK8 Kinase Activity Promotes Glycolysis.
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DOI：
10.1016/j.celrep.2017.10.058
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发表时间：
2017-11-07
期刊：
影响因子：
8.8
通讯作者：
Espinosa JM
中科院分区：
文献类型：
--
作者：
Galbraith MD;Andrysik Z;Pandey A;Hoh M;Bonner EA;Hill AA;Sullivan KD;Espinosa JM
有氧糖酵解，也被称为瓦尔堡效应，是癌组织的标志。尽管它在癌症发展中的重要性，我们对这种形式的代谢重编程驱动机制的理解是不完整的。我们在这里报告了一个分析结直肠癌细胞工程进行单点突变的活性位点的介体相关激酶CDK 8，创造亚型等位基因敏感的大体积ATP类似物。转录组分析显示，CDK 8激酶活性是糖酵解级联反应的许多组分表达所必需的。在常氧和缺氧中，CDK 8抑制损害葡萄糖转运蛋白表达、葡萄糖摄取、糖酵解能力和储备，以及细胞增殖和锚定非依赖性生长。重要的是，CDK 8损伤使细胞对药理学糖酵解抑制敏感，这一结果用Senexin A（CDK 8/CDK 19的双重抑制剂）重现。总而言之，这些结果有助于我们理解CDK 8作为一种致癌基因，并证明在高度糖酵解肿瘤中靶向CDK 8的研究是合理的。Galbraith等人使用化学遗传学方法来检查CDK 8激酶活性在癌细胞中的作用。CDK 8活性是编码葡萄糖代谢所需酶的多个基因转录所必需的。受损的CDK 8活性降低葡萄糖摄取和糖酵解，并使细胞对葡萄糖类似物2-脱氧-D-葡萄糖敏感。
Aerobic glycolysis, also known as the Warburg effect, is a hallmark of cancerous tissues. Despite its importance in cancer development, our understanding of mechanisms driving this form of metabolic reprogramming is incomplete. We report here an analysis of colorectal cancer cells engineered to carry a single point mutation in the active site of the Mediator-associated kinase CDK8, creating hypomorphic alleles sensitive to bulky ATP analogs. Transcriptome analysis revealed CDK8 kinase activity is required for expression of many components of the glycolytic cascade. CDK8 inhibition impairs glucose transporter expression, glucose uptake, glycolytic capacity and reserve, as well as cell proliferation and anchorage independent growth, both in normoxia and hypoxia. Importantly, CDK8 impairment sensitizes cells to pharmacological glycolysis inhibition, a result reproduced with Senexin A, a dual inhibitor of CDK8/CDK19. Altogether, these results contribute to our understanding of CDK8 as an oncogene and justify investigations to target CDK8 in highly glycolytic tumors. Galbraith et al. use a chemical genetics approach to examine the role of CDK8 kinase activity in cancer cells. CDK8 activity is required for transcription of multiple genes encoding enzymes required for glucose metabolism. Impaired CDK8 activity reduces glucose uptake and glycolysis, and sensitizes cells to the glucose analog 2-deoxy-D-glucose.
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