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p73 regulates serine biosynthesis in cancer

Oncogene volume 33, pages 5039–5046 (2014)Cite this article

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Abstract

Activation of serine biosynthesis supports growth and proliferation of cancer cells. Human cancers often exhibit overexpression of phosphoglycerate dehydrogenase (PHGDH), the metabolic enzyme that catalyses the reaction that diverts serine biosynthesis from the glycolytic pathway. By refueling serine biosynthetic pathways, cancer cells sustain their metabolic requirements, promoting macromolecule synthesis, anaplerotic flux and ATP. Serine biosynthesis intersects glutaminolysis and together with this pathway provides substrates for production of antioxidant GSH. In human lung adenocarcinomas we identified a correlation between serine biosynthetic pathway and p73 expression. Metabolic profiling of human cancer cell line revealed that TAp73 activates serine biosynthesis, resulting in increased intracellular levels of serine and glycine, associated to accumulation of glutamate, tricarboxylic acid (TCA) anaplerotic intermediates and GSH. However, at molecular level p73 does not directly regulate serine metabolic enzymes, but transcriptionally controls a key enzyme of glutaminolysis, glutaminase-2 (GLS-2). p73, through GLS-2, favors conversion of glutamine in glutamate, which in turn drives the serine biosynthetic pathway. Serine and glutamate can be then employed for GSH synthesis, thus the p73-dependent metabolic switch enables potential response against oxidative stress. In knockdown experiment, indeed, TAp73 depletion completely abrogates cancer cell proliferation capacity in serine/glycine-deprivation, supporting the role of p73 to help cancer cells under metabolic stress. These findings implicate p73 in regulation of cancer metabolism and suggest that TAp73 influences glutamine and serine metabolism, affecting GSH synthesis and determining cancer pathogenesis.

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Abbreviations

GLS-2:

Glutaminase 2

NSCLC:

non-small-cell lung carcinoma

PHGDH:

Phosphoglycerate dehydrogenase

PKM2:

M2 isoform of pyruvate kinase

PSAT-1:

phospho-serine aminotransferase 1

PSPH:

phospho-serine phosphatase

SGBS:

serine/glycine biosynthesis

TCA:

tricarboxylic acids.

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Acknowledgements

This work has been supported by the Medical Research Council, United Kingdom; MIUR, MinSan/IDI-IRCCS (RF73, RF57), ACC12, AIRC (2011-IG11955), AIRC 5xmille (MCO #9979) to GM Work was supported by Ministry of Education and Science of the Russian Federation (11.G34.31.0069) to GM & (14.B37.21.1967) to AAV.

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Author notes

  1. I Amelio and E K Markert: These authors contributed equally to this work.

Authors and Affiliations

  1. Medical Research Council, Toxicology Unit, Leicester University, Leicester, UK

    I Amelio, A Rufini, A V Antonov, B S Sayan, P Tucci, M Agostini & G Melino

  2. The Simons Center for Systems Biology, Institute for Advanced Study, Princeton, NJ, USA

    E K Markert & A J Levine

  3. Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester, UK

    A Rufini

  4. Molecular Pharmacology Laboratory, Technological University, St-Petersburg, Russia

    A V Antonov

  5. Division of Thoracic Surgery, University of Tor Vergata, Rome, Italy

    T C Mineo

  6. Department of Experimental Medicine and Surgery, University of Rome ‘Tor Vergata’, Rome, Italy

    G Melino

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Correspondence to G Melino.

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Amelio, I., Markert, E., Rufini, A. et al. p73 regulates serine biosynthesis in cancer. Oncogene 33, 5039–5046 (2014). https://doi.org/10.1038/onc.2013.456

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