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The breast cancer oncogene IKKε coordinates mitochondrial function and serine metabolism
- Source :
- EMBO Reports
- Publication Year :
- 2020
- Publisher :
- Wiley-VCH Verlag, 2020.
-
Abstract
- 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.<br />The IκB kinase IKKε inhibits mitochondrial metabolism by limiting pyruvate oxidation, in turn activating the serine biosynthesis pathway via ATF4 in a NFκB and IRF3‐independent manner.
- Subjects :
- IKKε
mitochondrial metabolism
Breast Neoplasms
IκB kinase
Activating Transcription Factor 4
Biology
environment and public health
Biochemistry
Article
Serine
03 medical and health sciences
0302 clinical medicine
breast cancer
Downregulation and upregulation
Genetics
Humans
ATF4
skin and connective tissue diseases
Molecular Biology
Transcription factor
030304 developmental biology
Cancer
0303 health sciences
Oncogene
Chemistry
Kinase
Phosphoproteomics
Articles
Oncogenes
I-kappa B Kinase
Mitochondria
enzymes and coenzymes (carbohydrates)
Metabolism
serine biosynthesis
Cancer research
Cytokine secretion
Female
biological phenomena, cell phenomena, and immunity
030217 neurology & neurosurgery
Signal Transduction
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- EMBO Reports
- Accession number :
- edsair.doi.dedup.....38d55148cdb8c11f109cfd0ce2067d7c