Abstract
The p53 tumor suppressor continues to be distinguished as the most frequently mutated gene in human cancer. It is widely believed that the ability of p53 to induce senescence and programmed cell death underlies the tumor suppressor functions of p53. However, p53 has a number of other functions that recent data strongly implicate in tumor suppression, particularly with regard to the control of metabolism and ferroptosis (iron- and lipid-peroxide-mediated cell death) by p53. As reviewed here, the roles of p53 in the control of metabolism and ferroptosis are complex. Wild-type (WT) p53 negatively regulates lipid synthesis and glycolysis in normal and tumor cells, and positively regulates oxidative phosphorylation and lipid catabolism. Mutant p53 in tumor cells does the converse, positively regulating lipid synthesis and glycolysis. The role of p53 in ferroptosis is even more complex: in normal tissues, WT p53 appears to positively regulate ferroptosis, and this pathway appears to play a role in the ability of basal, unstressed p53 to suppress tumor initiation and development. In tumors, other regulators of ferroptosis supersede p53’s role, and WT p53 appears to play a limited role; instead, mutant p53 sensitizes tumor cells to ferroptosis. By clearly elucidating the roles of WT and mutant p53 in metabolism and ferroptosis, and establishing these roles in tumor suppression, emerging research promises to yield new therapeutic avenues for cancer and metabolic diseases.
Highlights
The tumor suppressor gene TP53 has been the most heavily studied human gene since its discovery nearly 40 years ago [1]
Ferroptosis is a novel cell death pathway first characterized in 2012 and can be best described as an iron-dependent, caspase-independent form of cell death driven by the formation of p53, Metabolism, and Ferroptosis lipid peroxidation [4]
Two mouse models containing engineered mutations in p53 that eliminate the ability of p53 to induce apoptosis and senescence both retain the ability to suppress spontaneous tumor development; both of these mutants retain the ability to transactivate genes in metabolism and ferroptosis [5, 6]
Summary
The tumor suppressor gene TP53 has been the most heavily studied human gene since its discovery nearly 40 years ago [1]. P53’s role in the regulation of genes involved in metabolism and ferroptosis has been implicated in its ability to suppress tumor development. P53 directly binds and inhibits the enzyme glucose-6-phosphate dehydrogenase, suppressing glucose metabolism [12] It is clear from these and other studies that in normal, unstressed organisms, p53 directly regulates the metabolic state in a cell (Figure 1). One of the hallmarks of cancer is deregulated metabolism, generally demonstrated by this switch from aerobic glycolysis to oxidative phosphorylation Though this results in a lower and less efficient ATP yield, it is believed that cancer cells benefit by diverting glycolytic intermediates to biosynthetic pathways necessary for rapid cell division [16]. This metabolic switch leads to decreased mitochondria-mediated apoptosis and more efficient signaling through available metabolites in cancer cells [17]
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