Abstract
Metabolic reprogramming in cancer cells is controlled by the activation of multiple oncogenic signalling pathways in order to promote macromolecule biosynthesis during rapid proliferation. Cancer cells also need to adapt their metabolism to survive and multiply under the metabolically compromised conditions provided by the tumour microenvironment. The tumour suppressor p53 interacts with the metabolic network at multiple nodes, mostly to reduce anabolic metabolism and promote preservation of cellular energy under conditions of nutrient restriction. Inactivation of this tumour suppressor by deletion or mutation is a frequent event in human cancer. While loss of p53 function lifts an important barrier to cancer development by deleting cell cycle and apoptosis checkpoints, it also removes a crucial regulatory mechanism and can render cancer cells highly sensitive to metabolic perturbation. In this review, we will summarise the major concepts of metabolic regulation by p53 and explore how this knowledge can be used to selectively target p53 deficient cancer cells in the context of the tumour microenvironment.
Highlights
Mutants of p53, often found in tumours, lack this glucose-6-phosphate dehydrogenase (G6PD)-inhibitory activity. This leads to the activation of metabolite entry into the phosphate pathway (PPP) and directs glucose towards biosynthesis [51]. These results demonstrate that cancer cells need to accurately control the relative metabolite flux between glycolysis and the PPP to generate glycolytic intermediates and maintain NADPH
As a consequence, disrupting metabolic control mechanisms that maintain the balance of metabolite flux between glycolysis and PPP should selectively impair the survival of p53 deficient cancer cells and could be a strategy for therapeutic intervention
P53 promotes the conversion of pyruvate into acetyl-coenzyme A (CoA) for entry into the tricarboxylic acid (TCA) cycle and positively regulates glucose oxidation [69]
Summary
One of the hallmarks of cancer is the altered metabolic activity of cancer cells [31] and many cancer cells rely on glycolysis as the predominant source of ATP production, even in the presence of oxygen. This leads to the activation of metabolite entry into the PPP and directs glucose towards biosynthesis [51] Together, these results demonstrate that cancer cells need to accurately control the relative metabolite flux between glycolysis and the PPP to generate glycolytic intermediates and maintain NADPH regeneration and nucleotide biosynthesis. While acute activation of p53 in response to DNA damage temporarily increases the cellular demand for NADPH and nucleotides for DNA repair, loss or mutation of p53 in cancer enhances biosynthetic demand due to increased proliferation and requires similar metabolic adaptations This deregulation of metabolic activity renders p53 deficient cancer cells highly dependent on NADPH regenerating processes and makes them highly susceptible to perturbation. As a consequence, disrupting metabolic control mechanisms that maintain the balance of metabolite flux between glycolysis and PPP should selectively impair the survival of p53 deficient cancer cells and could be a strategy for therapeutic intervention
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
