To be, or not to be: functional dilemma of p53 metabolic regulation

Abstract

Purpose of review: In recent years, the emerging role of p53 in metabolic regulation has been a topic of great interest. Although apoptotic and growth arrest functions of p53 remain as important mechanisms for preserving genomic stability, metabolic functions of p53 show increasing potential in contributing to p53-mediated tumor suppression. Numerous recent studies provided further insights into the metabolic functions of p53 and their implications in tumorigenesis.

Recent findings: Several novel p53 metabolic targets have been identified that participate in various aspects of metabolism. Although some studies demonstrate the potential tumor suppressive function of p53 metabolic genes, others reveal prosurvival roles of those targets in both tumor and normal cells. Specifically, Tp53-induced glycolysis and apoptosis regulator (TIGAR) has been thought to promote tumor suppression through metabolic fine-tuning, yet, TIGAR-deficient mice display reduction in tumorigenesis. Finally, characterization of the 3KR mouse model underscored the significance of p53 metabolic regulation in tumor suppression, while also alluding to the potential mechanism for selective regulation of p53 metabolic targets.

Summary: Expression of many p53 metabolic genes elicits both antitumor and tumorigenic effects, suggesting that p53 may contribute to cellular protection as well as tumor suppression. Future studies must carefully dissect the duality of p53 metabolic function, which may potentially prove useful in designing cancer therapies.

Figure 1. p53 exerts a diverse array of metabolic functions

A broad spectrum of metabolic targets are regulated by p53, leading to various functional outcomes in tumor and normal physiology. Genes in blue boxes are previously-identified p53 targets, while those in green boxes are most recently discovered. Dashed line in the GLS2 axis illustrates the potential of this target in enhancing tumor survival based on its function. Abbr. OXPHOS, oxidative phosphorylation; S1P, sphingosine-1-phosphate; FAO, fatty acid oxidation; CoA, coenzyme A.

Figure 2. Opposing functions of p53 metabolic regulation

Metabolic regulation by p53 in tumorigenesis is a double-edged sword: maintaining oxidative balance and energy homeostasis could prevent cancer development in the pre-cancerous stage, but favors tumor survival after malignant transformation.

Figure 3. A hypothetical model of differential regulation by p53

p53 is subjected to a hierarchical sequence of post-translational modifications as stress level increases, which induces various functional outcome depending on the combination of modifications (see text for complete description).