Tumor suppressor p53 and its mutants in cancer metabolism

Abstract

Tumor-suppressor p53 plays a key role in tumor prevention. As a transcription factor, p53 transcriptionally regulates its target genes to initiate different biological processes in response to stress, including apoptosis, cell cycle arrest or senescence, to exert its function in tumor suppression. Recent studies have revealed that metabolic regulation is a novel function of p53. Metabolic changes have been regarded as a hallmark of tumors and a key contributor to tumor development. p53 regulates many different aspects of metabolism, including glycolysis, mitochondrial oxidative phosphorylation, pentose phosphate pathway, fatty acid synthesis and oxidation, to maintain the homeostasis of cellular metabolism, which contributes to the role of p53 in tumor suppression. p53 is frequently mutated in human tumors. In addition to loss of tumor suppressive function, tumor-associated mutant p53 proteins often gain new tumorigenic activities, termed gain-of-function of mutant p53. Recent studies have shown that mutant p53 mediates metabolic changes in tumors as a novel gain-of-function to promote tumor development. Here we review the functions and mechanisms of wild-type and mutant p53 in metabolic regulation, and discuss their potential roles in tumorigenesis.

Keywords: Metabolism; Mutant p53; Tumor suppressor; p53.

Fig. 1

Tumor suppressor p53 and its signaling pathway. In unstressed cells, p53 protein is kept at a low level by different negative regulators, including E3 ubiquitin ligases MDM2, Cop1 and Pirh2. In response to a wild variety of stress signals, p53 is activated and accumulated in cells. The activated p53 then binds to p53 responsive elements (p53 REs) in its target genes to transcriptionally regulate their expression, which in turn regulates various biological processes, including cell cycle arrest, DNA repair, apoptosis, senescence and metabolism.

Fig. 2

The regulation of cellular metabolism by p53. p53 regulates glycolysis, mitochondrial oxidative phosphorylation, pentose phosphate pathway (PPP), and lipid metabolism in cells. p53 represses glycolysis through inducing the expression of TIGAR and Parkin and repressing the expression of GLUT1 & 4, PGM, PDK2, and MCT1. Furthermore, p53 negatively regulates the AKT/mTOR signaling to repress glycolysis, and negatively regulates the NF-κB signaling to repress the expression of GLUT3. p53 transcriptionally induces SCO2, AIF, p53R2, Mieap, Parkin and GLS2, and represses the expression of ME1 and ME2 to promote mitochondrial oxidative phosphorylation. p53 physically interacts with G6PD and inhibits its activity to negatively regulate the PPP pathway. p53 induces the expression of LPIN1 and GAMT to enhance fatty acid oxidation, and represses the expression of SREBP1c to inhibit fatty acid synthesis. In addition, p53 negatively regulates fatty acid synthesis through inhibition of the mTOR and PPP pathways.

Fig. 3

The regulation of metabolism by gain-of-function mutant p53. Tumor- associated mutant p53 binds and activates SREBPs, which induce the expression of many genes in the mevalonate pathway, a pathway that regulates lipid metabolism. Furthermore, mutant p53 activates the RhoA/ROCK signaling, which in turn stimulates the translocation of GLUT1 to the plasma membrane, and thereby promotes glycolysis and the Warburg effect in tumor cells. The activation of the mevalonate pathway and glycolysis by mutant p53 contributes to the role of mutant p53 in tumorigenesis.