WIN 18446 The recent identification of new mechanisms for tr

The recent identification of new mechanisms for triggering ferroptosis, by compounds termed FIN56 and FINO2, provided new insights into regulation of ferroptosis. FINO2 acts through a distinct mechanism: it promotes lipid peroxidation by oxidizing iron and indirectly inactivating GPX4 [180]. FIN56 was found to trigger ferroptosis by inducing a combined effect of mediating the depletion of both GPX4 protein and the mevalonate-derived antioxidant coenzyme Q10 (CoQ10) [172]. CoQ10 is an endogenously-produced lipid-soluble antioxidant, which was shown to prevent the harmful oxidation of proteins, lipids and DNA [181], [182]. Importantly, in addition to its direct antioxidant activity, CoQ10 also contributes to regeneration of other antioxidants such as ascorbate and α-tocopherol [183]. The role for cellular CoQ10 pool in regulating ferroptotic death remains to be explored.
Possible biological functions of ferroptosis
Open questions
Acknowledgments The research of B.R.S. was funded by National Institutes of Health/National Cancer Institute Grants 1R35CA209896 and P01CA087497.
Introduction Discovered in the 1970s, the tumor suppressor protein p53 (TP53) plays a critical role in the cellular response to various stresses, including DNA damage, hypoxia, nutrition starvation, and oncogene activation [1]. Activation of p53 can lead to survival or death, depending on the levels of stress [2]. Low levels of stress or damage trigger p53 activation to induce WIN 18446 arrest, DNA repair, and survival. p53 can protect against oxidative stress-induced DNA damage and death via downregulation of the production of reactive oxygen species (ROS) in cells. In contrast, high levels of stress or injury result in the activation of p53 to induce apoptosis and death. Unfortunately, p53 is usually mutated or depleted in many cancers, which limits the antitumor function of p53. Many studies have been focusing on the identification of p53 target genes that mediate tumor suppressor function. In addition to acting as a transactional factor in the nucleus, transcription-independent functions of cytosolic p53 are documented in the processes controlling cell death and metabolism, including apoptosis and autophagy [3]. For example, cytosolic p53 can directly bind to pro-apoptotic members of the BCL-2 family (BAX [BCL2 associated X, apoptosis regulator] and BBC3/PUMA [BCL2 binding component 3]) to increase mitochondrial membrane permeabilization and the release of pro-apoptotic factors from the mitochondria [4], [5]. Unlike nuclear p53, which acts as an autophagy-promoting transcription factor [6], [7], cytosolic p53 can block autophagy in response to nutrient starvation or mTOR inhibition [8]. These context-dependent roles of p53 in survival and death are regulated in a fine-tuned manner by its ubiquitination, phosphorylation, acetylation, and other modifications [9], [10]. Over the last three years, studies in both cell cultures and animal models have established that p53 represents a novel regulator of ferroptosis [11], [12], [13], [14] (Fig. 1), a form of regulated cell death characterized by the accumulation of lethal iron or lipid hydroperoxides (e.g., PUFA-OOH) [15]. In this review, we will summarize the molecular mechanism of ferroptosis and focus on the current understanding of connections between p53 and ferroptosis and its potential as a target in cancer therapy.
Ferroptosis basics Since its discovery in 2012 [15], the study of ferroptosis has been a fast-growing field in cell death research [16]. The process and function of ferroptosis, as well as its impact in disease susceptibility, has been recently well-reviewed [17], [18]. We first briefly introduce the major inducers and regulators of ferroptosis.
Inducers
Regulators
Pro-death function of p53 in ferroptosis
Promotion of SAT1 expression The low-molecular-weight polyamines, including putrescine, spermidine and spermine, are implicated in the regulation of cellular growth, proliferation, and differentiation. At the molecular level, SAT1 (spermidine/Spermine N1-acetyltransferase 1) is an important regulator in polyamine metabolism through acetylating spermidine and spermine using acetyl-coenzyme A [70]. Impaired polyamine metabolism and abnormal SAT1 expression is associated with various pathological conditions, including cancer [70]. The activity of SAT1 is increased in response to various stresses, including oxidative stress, heat shock, and inflammatory stimuli. Previous studies have observed that overexpression of SAT1 results in rapid depletion of cellular spermidine and spermine, which cause significant growth inhibition and mitochondrial apoptosis [71]. Recent research studies have found that SAT1 is a transcriptional target of p53 in MCF7, U2OS, A375 (a human melanoma cell line), and H1299 cells (a human lung cancer cell line) (Fig. 1) [13]. However, only ferrostatin-1, but not other cell death inhibitors (Z-VAD-FMK, necrostatin-1, and 3-methyladenine), can inhibit ROS-induced cell death in SAT1 Tet-on cells [13]. SAT1 depletion also inhibits p53- and p533KR-induced ferroptosis [13]. Mechanistically, SAT1 has no effects on the expression and activity of SLC7A11 and GPX4 [13]. In contrast, SAT1 induction correlates with the expression levels of ALOX15 (arachidonate 15-lipoxygenase), but not ALOX5 and ALOX12 [13]. Pharmacologic inhibition of ALOX15 by PD146176 attenuates SAT1-mediated ferroptosis, indicating that ALOX15 is a downstream effector of p53-induced SAT1 expression in ferroptosis [13]. However, how cancer cells activate this p53-SAT1-ALOX15 metabolic pathway and the molecular cues behind the ferroptosis have largely remained obscure.