The role of tumor suppressor p53 in the antioxidant defense and metabolism

Abstract

Tumor suppressor p53 is inactivated in most cancers and the critical role of p53 in the suppression of carcinogenesis has been confirmed in many mouse models. The protein product of the tumor suppressor p53 gene works as a transcriptional regulator, activating expression of numerous genes involved in cell death, cell cycle arrest, senescence, DNA-repair and many other processes. In spite of the multiple efforts to characterize the functions of p53, the mechanisms of tumor suppression by p53 are still elusive. Recently, new activities of p53 such as regulation of reactive oxygen species (ROS) and metabolism have been described and the p53-regulated genes responsible for these functions have been identified. Metabolic derangements and accumulation of ROS are features of carcinogenesis, supporting the idea that many tumor suppressive effects of p53 can be mediated by regulation of metabolism and/or ROS. Mutations in the p53 gene can not only inactivate wild type function of p53 but also endow p53 with new functions such as activation of new metabolic pathways contributing to carcinogenesis. Understanding the metabolic and antioxidant functions of p53 allows us to develop approaches to restore p53 function in cancers, where p53 is inactivated, in other to ensure the best outcome of anti-cancer treatment.

Figure 1. Yin and Yang activities of p53 in tumor suppression

Many stress insults induce p53 which activates expression of multiple genes via interaction with p53-responsive elements on their promoters. The outcome of p53 activation can be cell protection or cell death depending on the nature and intensity of the stress. Both processes can be required to reach maximal protection of the organism against carcinogenesis.

Figure 2. Regulation of anti-oxidant and pro-oxidant genes by p53

Low-intensities of stress stimulate expression of highly sensitive p53-dependent pro- survival genes involved in ROS suppression, metabolism, mitochondrial function and autophagy, which protect cell viability. Highly intense stress insults activate cell death via the induction of pro-apoptotic and pro-oxidant genes. In response to low stress, PGC1α binds p53 and stimulates expression of pro-survival genes, although its degradation induced by chronic prolonged stress may be responsible for the activation of genes responsible for cell death.

Figure 3. p53 plays an important role in adaptation to metabolic derangements

A shortage in metabolites such as glucose, glutamine and serine activate p53 which tune up metabolism to suppress undesired anabolic processes via the inhibition of mTORC1, stimulate ATP production via mitochondrial respiration rather than glycolysis, and use alternative fatty acid oxidation as other sources of ATP production. Dysregulation of these processes due to p53 inactivation in cancer cells can be beneficial for tumor growth.

Figure 4. Mutant p53 can contribute to carcinogenesis via gain-of-function mechanism

Hot-spot p53 mutants can regulate metabolism, suppress mitochondrial respiration, stimulate ROS production and protect against anti-cancer therapy. These activities are mediated by an interaction with different transcription factors such as: SREBP, critical for activation of mevalonate pathway, as well as NRF2 and Tap73, involved in control of mitochondrial respiration and antioxidant defense. Mutant p53 can also activate the promoter of the dUTPase gene, inducing the expression of enzyme dUTPase which suppresses therapeutic effects of fluoropyrimidine anticancer drugs.