CDK9 Inhibition Induces a Metabolic Switch that Renders Prostate Cancer Cells Dependent on Fatty Acid Oxidation
CDK9 Inhibition Induces a Metabolic Switch that Renders Prostate Cancer Cells Dependent on Fatty Acid Oxidation
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DOI：
10.1016/j.neo.2019.05.001
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发表时间：
2019-07-01
期刊：
影响因子：
4.8
通讯作者：
Mills, Ian G.
中科院分区：
文献类型：
--
作者：
Itkonen, Harri M.;Poulose, Ninu;Mills, Ian G.
细胞周期蛋白依赖性激酶9（CDK 9）是RNA聚合酶II的关键调节因子，是由转录失调驱动的癌症的候选药物靶标。在这里，我们报告了前列腺癌细胞对CDK 9抑制的反应的多组学分析，以确定合成的致命相互作用。这些相互作用进行了验证，使用活细胞成像，线粒体流量，活力和细胞死亡激活测定。我们发现，CDK 9抑制诱导前列腺癌细胞的急性代谢应激。这表现为线粒体氧化磷酸化的急剧下调、ATP耗竭和AMP活化蛋白激酶（AMPK）（细胞能量稳态的关键传感器）的快速和持续磷酸化的诱导。我们使用代谢组学来证明CDK 9的抑制导致脂肪酸氧化（FAO）中的代谢中间体酰基肉毒碱的积累。酰基-肉毒碱由肉毒碱棕榈酰转移酶1和2（CPT）产生，并且我们使用遗传和药理学工具来显示CPT活性的抑制与CDK 9抑制是合成致死的。据我们所知，这是第一份显示CDK 9抑制显著改变癌细胞代谢的报告。
Cyclin-dependent kinase 9 (CDK9), a key regulator of RNA-polymerase II, is a candidate drug target for cancers driven by transcriptional deregulation. Here we report a multi-omics-profiling of prostate cancer cell responses to CDK9 inhibition to identify synthetic lethal interactions. These interactions were validated using live-cell imaging, mitochondrial flux-, viability- and cell death activation assays. We show that CDK9 inhibition induces acute metabolic stress in prostate cancer cells. This is manifested by a drastic down-regulation of mitochondrial oxidative phosphorylation, ATP depletion and induction of a rapid and sustained phosphorylation of AMP-activated protein kinase (AMPK), the key sensor of cellular energy homeostasis. We used metabolomics to demonstrate that inhibition of CDK9 leads to accumulation of acyl-carnitines, metabolic intermediates in fatty acid oxidation (FAO). Acyl-carnitines are produced by carnitine palmitoyltransferase enzymes 1 and 2 (CPT), and we used both genetic and pharmacological tools to show that inhibition of CPT-activity is synthetically lethal with CDK9 inhibition. To our knowledge this is the first report to show that CDK9 inhibition dramatically alters cancer cell metabolism.