Ironing out how p53 regulates ferroptosis

Abstract

Since it was first found capable of suppressing transformation by E1A and RAS oncogenes (1), and then shortly thereafter discovered to be mutationally inactivated in over half of all human tumors (2), uncovering how the TP53 tumor suppressor (hereafter p53) inhibits tumor initiation and progression has remained one of the holy grails of the cancer field. At no point in this journey has p53 been readily forthcoming about its secret tumor-suppressor activities, and there have been many twists and turns along the way. In PNAS, Ou et al. (3) take us one step toward what recent data indicate might be the correct pathway of tumor suppression, with their identification of SAT1 (spermidine/spermine N 1-acetyltransferase 1), a mediator of polyamine catabolism, and ALOX15 (arachidonate 15-lipoxygenase), a lipid oxygenase, in a recently identified activity of p53 in the regulation of ferroptosis. Ferroptosis is an iron-mediated, caspase-independent, pathway of cell death that requires the accumulation of reactive oxygen species (ROS) and lipid peroxides. This pathway was first discovered by Stockwell and colleagues in 2012 (4), and this group later showed that this pathway was controlled by GPX4, a glutathione-regulated lipid repair enzyme (5). In 2015, Gu and colleagues implicated ferroptosis as a critical component of tumor suppression by p53 (6). However, before describing the collision between the fields of p53 and ferroptosis, it would be informative to analyze the data of Ou et al. (3) in a historical context, by highlighting the 27-year search for the key activities of p53 in tumor suppression. Throughout this quest, scientists focused on two questions: first, what stimulus does p53 “sense” when it becomes activated to suppress tumor development? And second, what key target genes does p53 regulate to eliminate the precancerous cell? Some of the first-described p53 target genes that were found to align in … [↵][1]1Email: mmurphy{at}wistar.org. [1]: #xref-corresp-1-1