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p73 regulates serine biosynthesis in cancer.

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journal contribution
posted on 29.05.2020, 10:26 by I Amelio, EK Markert, A Rufini, AV Antonov, BS Sayan, P Tucci, M Agostini, TC Mineo, AJ Levine, G Melino
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.

Funding

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.

History

Citation

Oncogene, 2014, 33 (42), pp. 5039-5046

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Cancer Studies and Molecular Medicine

Version

AM (Accepted Manuscript)

Published in

Oncogene

Volume

33

Issue

42

Pagination

5039-5046

Publisher

Springer Nature

eissn

1476-5594

Acceptance date

24/09/2013

Copyright date

2013

Language

eng

Publisher version

https://www.nature.com/articles/onc2013456