p73 regulates serine biosynthesis in cancer

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.

Vascular ageing and endothelial cell senescence: Molecular mechanisms of physiology and diseases

“…Metabolic regulation by p53 family appears a key function for their cancer-related but also ageing-related phenotype. All the three members promote mitochondrial respiration thought regulation of different metabolic enzymes, including the glutaminase 2 (Gls2) (Adamovich et al, 2014;Amelio et al, 2014b;Bellomaria et al, 2010Bellomaria et al, , 2012Giacobbe et al, 2013;He et al, 2013;Hu et al, 2010;Sharif et al, 2015;Simon et al, 2014;Velletri et al, 2013;Viticchie et al, 2015). Gls2 regulates glutamine utilization, supplying anaplerotic flux of substrates resulting in promotion of mitochondrial activity and ATP synthesis (Amelio et al, 2014a;Maniam et al, 2015).…”

Uncovering metabolism in rhabdomyosarcoma

“…The GSH-dependent antioxidant response of cancer cells may benefit depending on the availability of serine, which can be transformed into glycine through the serine hydroxymethyltransferase (SHMT). [104][105][106] Interestingly, it has been demonstrated that cancer cells lacking p53 are protected from oxidative stress-induced by serine depletion in the presence of p73, a p53 family member that has the ability to drive serine biosynthesis de novo 107,108 and to increase the pentose phosphate shunt and nucleotide biosynthesis via G6PD. 109,110 Thus, the p73 overexpression detected in various primary RMS samples 111 may have an important role for oxidative stress resistance.…”

cMyc-mediated activation of serine biosynthesis pathway is critical for cancer progression under nutrient deprivation conditions

“…It was reported recently that, upon serine starvation, p53 activates p21 to promote GSH production to combat ROS [25,26]. Additionally, p73, ATF4, G9A, HIF1 and PKCζ were also reported to regulate serine biosynthesis and metabolism [27][28][29][30][31]. However, compared to the profound understanding of glycolysis and glutaminolysis in cancer cells, we are only beginning to appreciate the critical impact of serine synthesis pathway (SSP) on cancer progression.…”