IκB kinase ε (IKKε) is a key molecule at the crossroads of inflammation and cancer. Known to regulate cytokine secretion via NFκB and IRF3, the kinase is also a breast cancer oncogene, overexpressed in a variety of tumours. However, to what extent IKKε remodels cellular metabolism is currently unknown. Here, we used metabolic tracer analysis to show that IKKε orchestrates a complex metabolic reprogramming that affects mitochondrial metabolism and consequently serine biosynthesis independently of its canonical signalling role. We found that IKKε upregulates the serine biosynthesis pathway (SBP) indirectly, by limiting glucose‐derived pyruvate utilisation in the TCA cycle, inhibiting oxidative phosphorylation. Inhibition of mitochondrial function induces activating transcription factor 4 (ATF4), which in turn drives upregulation of the expression of SBP genes. Importantly, pharmacological reversal of the IKKε‐induced metabolic phenotype reduces proliferation of breast cancer cells. Finally, we show that in a highly proliferative set of ER negative, basal breast tumours, IKKε and PSAT1 are both overexpressed, corroborating the link between IKKε and the SBP in the clinical context.

中文翻译：

---

乳腺癌癌基因 IKKε 协调线粒体功能和丝氨酸代谢。

IκB 激酶 ε (IKKε) 是炎症和癌症交汇处的关键分子。已知通过 NFκB 和 IRF3 调节细胞因子分泌，该激酶也是一种乳腺癌癌基因，在多种肿瘤中过度表达。然而，目前尚不清楚 IKKε 在多大程度上重塑了细胞代谢。在这里，我们使用代谢示踪分析表明 IKKε 协调复杂的代谢重编程，影响线粒体代谢，从而影响丝氨酸的生物合成，而与其典型的信号传导作用无关。我们发现 IKKε 通过限制 TCA 循环中葡萄糖衍生的丙酮酸利用，抑制氧化磷酸化，间接上调丝氨酸生物合成途径 (SBP)。线粒体功能的抑制诱导激活转录因子 4 (ATF4)，这反过来又推动了 SBP 基因表达的上调。重要的是，IKKε 诱导的代谢表型的药理学逆转可减少乳腺癌细胞的增殖。最后，我们表明，在一组高度增殖的 ER 阴性基底乳腺肿瘤中，IKKε 和 PSAT1 均过表达，证实了临床背景下 IKKε 和 SBP 之间的联系。