PT  - JOURNAL ARTICLE
AU  - Ruoyan Xu
AU  - William Jones
AU  - Ewa Wilcz-Villega
AU  - A. Sofia H. Costa
AU  - Vinothini Rajeeve
AU  - Robert B. Bentham
AU  - Kevin Bryson
AU  - Ai Nagano
AU  - Busra Yaman
AU  - Sheila Olendo Barasa
AU  - Yewei Wang
AU  - Claude Chelala
AU  - Pedro Cutillas
AU  - Gyorgy Szabadkai
AU  - Christian Frezza
AU  - Katiuscia Bianchi
TI  - The breast cancer oncogene IKKε coordinates mitochondrial function and serine metabolism
AID  - 10.1101/855361
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 855361
4099  - http://biorxiv.org/content/early/2019/11/26/855361.short
4100  - http://biorxiv.org/content/early/2019/11/26/855361.full
AB  - The IκB kinase ε (IKKε) 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 IKKε remodels cellular metabolism is currently unknown. Here we used a combination of metabolomics and phosphoproteomics to show that IKKε orchestrates a complex metabolic reprogramming that affects mitochondrial metabolism and serine biosynthesis. Acting independently of its canonical signalling role, IKKε 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 IKKε-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, IKKε and PSAT1 expression levels are positively correlated corroborating the link between IKKε and the SBP in the clinical context.