TAp73 promotes anabolism

// Ivano Amelio 1 , Alexey A. Antonov 1 , Maria Valeria Catani 2 , Renato Massoud 2 , Francesca Bernassola 2 , Richard A. Knight 1 , Gerry Melino 1, 2, 3 , Alessandro Rufini 1, 4 1 Medical Research Council, Toxicology Unit, Leicester University, Leicester LE1 9HN, UK 2 Biochemistry Laboratory, IDI-IRCCS, University of Rome Tor Vergata, Rome 00133, Italy 3 Molecular Pharmacology Laboratory, Technological University, St-Petersburg, Russia 4 Department of Cancer Studies, Cancer Research UK, Leicester Centre, University of Leicester, Leicester, LE1 7RH, UK Correspondence to: Gerry Melino, e-mail: gm89@le.ac.uk Alessandro Rufini, e-mail: ar230@le.ac.uk Keywords: p73, p53, Metabolism, Warburg effect, cancer Received: October 27, 2014 Accepted: October 28, 2014 Published: November 13, 2014 ABSTRACT Metabolic adaptation has emerged as a hallmark of cancer and a promising therapeutic target, as rapidly proliferating cancer cells adapt their metabolism increasing nutrient uptake and reorganizing metabolic fluxes to support biosynthesis. The transcription factor p73 belongs to the p53-family and regulates tumorigenesis via its two N-terminal isoforms, with (TAp73) or without (ΔNp73) a transactivation domain. TAp73 acts as tumor suppressor, at least partially through induction of cell cycle arrest and apoptosis and through regulation of genomic stability. Here, we sought to investigate whether TAp73 also affects metabolic profiling of cancer cells. Using high throughput metabolomics, we unveil a thorough and unexpected role for TAp73 in promoting Warburg effect and cellular metabolism. TAp73-expressing cells show increased rate of glycolysis, higher amino acid uptake and increased levels and biosynthesis of acetyl-CoA. Moreover, we report an extensive TAp73-mediated upregulation of several anabolic pathways including polyamine and synthesis of membrane phospholipids. TAp73 expression also increases cellular methyl-donor S-adenosylmethionine (SAM), possibly influencing methylation and epigenetics, and promotes arginine metabolism, suggestive of a role in extracellular matrix (ECM) modeling. In summary, our data indicate that TAp73 regulates multiple metabolic pathways that impinge on numerous cellular functions, but that, overall, converge to sustain cell growth and proliferation.