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The breast cancer oncogene IKKε coordinates mitochondrial function and serine metabolism

Ruoyan Xu, William Jones, Ewa Wilcz-Villega, A. Sofia H. Costa, Vinothini Rajeeve, Robert B. Bentham, Kevin Bryson, Ai Nagano, Busra Yaman, Sheila Olendo Barasa, Yewei Wang, Claude Chelala, Pedro Cutillas, Gyorgy Szabadkai, Christian Frezza, Katiuscia Bianchi
doi: https://doi.org/10.1101/855361
Ruoyan Xu
1Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
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William Jones
1Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
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Ewa Wilcz-Villega
1Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
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A. Sofia H. Costa
3Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, United Kingdom
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Vinothini Rajeeve
2Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
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Robert B. Bentham
4Department of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College London, WC1E 6BT London, UK
5Francis Crick Institute, NW1 1AT, London UK
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Kevin Bryson
6Department of Computer Sciences, University College London, London WC1E 6BT, UK
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Ai Nagano
1Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
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Busra Yaman
1Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
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Sheila Olendo Barasa
1Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
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Yewei Wang
1Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
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Claude Chelala
1Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
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Pedro Cutillas
2Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
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Gyorgy Szabadkai
4Department of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College London, WC1E 6BT London, UK
5Francis Crick Institute, NW1 1AT, London UK
7Department of Biomedical Sciences, University of Padua, 35131 Padua, Italy
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Christian Frezza
3Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, United Kingdom
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Katiuscia Bianchi
1Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
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  • For correspondence: k.bianchi@qmul.ac.uk
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ABSTRACT

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.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted November 26, 2019.
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The breast cancer oncogene IKKε coordinates mitochondrial function and serine metabolism
Ruoyan Xu, William Jones, Ewa Wilcz-Villega, A. Sofia H. Costa, Vinothini Rajeeve, Robert B. Bentham, Kevin Bryson, Ai Nagano, Busra Yaman, Sheila Olendo Barasa, Yewei Wang, Claude Chelala, Pedro Cutillas, Gyorgy Szabadkai, Christian Frezza, Katiuscia Bianchi
bioRxiv 855361; doi: https://doi.org/10.1101/855361
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The breast cancer oncogene IKKε coordinates mitochondrial function and serine metabolism
Ruoyan Xu, William Jones, Ewa Wilcz-Villega, A. Sofia H. Costa, Vinothini Rajeeve, Robert B. Bentham, Kevin Bryson, Ai Nagano, Busra Yaman, Sheila Olendo Barasa, Yewei Wang, Claude Chelala, Pedro Cutillas, Gyorgy Szabadkai, Christian Frezza, Katiuscia Bianchi
bioRxiv 855361; doi: https://doi.org/10.1101/855361

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