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.

中文翻译：

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CDK9抑制诱导代谢开关，使前列腺癌细胞依赖于脂肪酸氧化。

细胞周期蛋白依赖性激酶9（CDK9）是R​​NA聚合酶II的关键调节剂，是转录失调驱动的癌症的候选药物靶标。在这里，我们报告前列腺癌细胞对CDK9抑制的反应的多组学分析，以鉴定合成的致死性相互作用。这些相互作用已通过活细胞成像，线粒体通量，生存力和细胞死亡激活分析进行了验证。我们表明，CDK9抑制诱导前列腺癌细胞中的急性代谢应激。这通过线粒体氧化磷酸化的急剧下调，ATP耗竭以及对AMP激活的蛋白激酶（AMPK）（细胞能量稳态的关键传感器）的快速持续磷酸化的诱导来证明。我们使用代谢组学来证明对CDK9的抑制会导致酰基肉碱的积累，脂肪酸氧化中的代谢中间体（FAO）。酰基肉碱是由肉碱棕榈酰转移酶1和2（CPT）产生的，我们同时使用了遗传和药理学工具来证明抑制CPT活性与CDK9抑制作用是合成致死的。据我们所知，这是第一个显示CDK9抑制会显着改变癌细胞代谢的报告。