The breast cancer oncogene IKKε coordinates mitochondrial function and serine metabolism

The IκB kinase e (IKKe) is a key molecule at the crossroads of inflammation and cancer. Known for its role as an activator of NFκB and IRF3 signalling leading to cytokine secretion, the kinase is also a breast cancer oncogene, overexpressed in a variety of tumours. However, to what extent IKKe remodels cellular metabolism is currently unknown. Here we used a combination of metabolomics and phosphoproteomics to show that IKKe orchestrates a complex metabolic reprogramming that affects mitochondrial metabolism and serine biosynthesis. Acting independently of its canonical signalling role, IKKe upregulates the serine biosynthesis pathway (SBP) mainly by limiting glucose and pyruvate derived anaplerosis of the TCA cycle. In turn, this elicits activation of the transcription factor ATF4 and upregulation of the SBP genes. Importantly, pharmacological inhibition of the IKKe-induced metabolic phenotype reduces proliferation of breast cancer cells. Finally, we show that in a set of basal ER negative and highly proliferative human breast cancer tumours, IKKe and PSAT1 expression levels are positively correlated corroborating the link between IKKe and the SBP in the clinical context.