Upregulation and activation of p53 by erastin‑induced reactive oxygen species contribute to cytotoxic and cytostatic effects in A549 lung cancer cells

Huang, Chaoli; Yang, Mengchang; Deng, Jia; Li, Peng; Su, Wenjie; Jiang, Rong

doi:10.3892/or.2018.6585

Cited by 67 publications

(65 citation statements)

References 22 publications

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“…This may explain the slight cytotoxic effects that dynasore treatment alone induces in our cellular systems. Although some studies have shown that erastin disrupts mPTP and induces apoptotic death of different cancer cells [ 44 , 45 ], our data clearly demonstrate that erastin induces ferroptosis in our cellular system and no other forms of regulated-cell death.…”

Section: Discussioncontrasting

confidence: 45%

Dynasore Blocks Ferroptosis through Combined Modulation of Iron Uptake and Inhibition of Mitochondrial Respiration

Clemente

Rabenau

Tang

et al. 2020

Cells

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Ferroptosis is a form of regulated necrosis characterized by a chain-reaction of detrimental membrane lipid peroxidation following collapse of glutathione peroxidase 4 (Gpx4) activity. This lipid peroxidation is catalyzed by labile ferric iron. Therefore, iron import mediated via transferrin receptors and both, enzymatic and non-enzymatic iron-dependent radical formation are crucial prerequisites for the execution of ferroptosis. Intriguingly, the dynamin inhibitor dynasore, which has been shown to block transferrin receptor endocytosis, can protect from ischemia/reperfusion injury as well as neuronal cell death following spinal cord injury. Yet, it is unknown how dynasore exerts these cell death-protective effects. Using small interfering RNA suppression, lipid reactive oxygen species (ROS), iron tracers and bona fide inducers of ferroptosis, we find that dynasore treatment in lung adenocarcinoma and neuronal cell lines strongly protects these from ferroptosis. Surprisingly, while the dynasore targets dynamin 1 and 2 promote extracellular iron uptake, their silencing was not sufficient to block ferroptosis suggesting that this route of extracellular iron uptake is dispensable for acute induction of ferroptosis and dynasore must have an additional off-target activity mediating full ferroptosis protection. Instead, in intact cells, dynasore inhibited mitochondrial respiration and thereby mitochondrial ROS production which can feed into detrimental lipid peroxidation and ferroptotic cell death in the presence of labile iron. In addition, in cell free systems, dynasore showed radical scavenger properties and acted as a broadly active antioxidant which is superior to N-acetylcysteine (NAC) in blocking ferroptosis. Thus, dynasore can function as a highly active inhibitor of ROS-driven types of cell death via combined modulation of the iron pool and inhibition of general ROS by simultaneously blocking two routes required for ROS and lipid-ROS driven cell death, respectively. These data have important implications for the interpretation of studies observing tissue-protective effects of this dynamin inhibitor as well as raise awareness that off-target ROS scavenging activities of small molecules used to interrogate the ferroptosis pathway should be taken into consideration.

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Section: Discussioncontrasting

confidence: 45%

Dynasore Blocks Ferroptosis through Combined Modulation of Iron Uptake and Inhibition of Mitochondrial Respiration

Clemente

Rabenau

Tang

et al. 2020

Cells

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“…Some studies have shown that p53 can be activated by ferroptosis inducers or inhibitors. For example, it was reported that erastin can induce p53 protein levels and increase p53 transcriptional activity towards its target genes, including p21 and Bax, in human lung cancer A549 cells [134]. Treating cells with ROS scavenger N-acetyl-1-cysteine (NAC) abolishes the effect of erastin on p53 levels, which suggests that enhancing the ROS levels is a mechanism contributing to p53 activation by erastin [134].…”

Section: P53 Regulation In Response To Ferroptosis Stimuli and Inhibimentioning

confidence: 99%

“…For example, it was reported that erastin can induce p53 protein levels and increase p53 transcriptional activity towards its target genes, including p21 and Bax, in human lung cancer A549 cells [134]. Treating cells with ROS scavenger N-acetyl-1-cysteine (NAC) abolishes the effect of erastin on p53 levels, which suggests that enhancing the ROS levels is a mechanism contributing to p53 activation by erastin [134]. Compound D13, a derivative of the triterpene saponin natural compound Albiziabioside A, was reported to induce ferroptosis through suppressing GPX4 expression in human HCT116 colorectal cancer cells [135].…”

Section: P53 Regulation In Response To Ferroptosis Stimuli and Inhibimentioning

confidence: 99%

The Regulation of Ferroptosis by Tumor Suppressor p53 and its Pathway

Liu

Zhang

Wang

et al. 2020

IJMS

168

124

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Tumor suppressor p53 plays a key role in tumor suppression. In addition to tumor suppression, p53 is also involved in many other biological and pathological processes, such as immune response, maternal reproduction, tissue ischemia/reperfusion injuries and neurodegenerative diseases. While it has been widely accepted that the role of p53 in regulation of cell cycle arrest, senescence and apoptosis contributes greatly to the function of p53 in tumor suppression, emerging evidence has implicated that p53 also exerts its tumor suppressive function through regulation of many other cellular processes, such as metabolism, anti-oxidant defense and ferroptosis. Ferroptosis is a unique iron-dependent form of programmed cell death driven by lipid peroxidation in cells. Ferroptosis has been reported to be involved in cancer, tissue ischemia/reperfusion injuries and neurodegenerative diseases. Recent studies have shown that ferroptosis can be regulated by p53 and its signaling pathway as well as tumor-associated mutant p53. Interestingly, the regulation of ferroptosis by p53 appears to be highly context-dependent. In this review, we summarize recent advances in the regulation of ferroptosis by p53 and its signaling pathway. Further elucidation of the role and molecular mechanism of p53 in ferroptosis regulation will yield new therapeutic strategies for cancer and other diseases, including neurodegenerative diseases and tissue ischemia/reperfusion injuries.

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“…SLC7A11 is a major component of System X C − and the latter is indispensable for importing cystine, which is used to synthesize antioxidant GSH [19,44]. Previous studies have demonstrated that p53 directs the transcriptionally suppressed SLC7A11 expression [41,45,46], thereby suppressing system X C − activity to trigger ferroptosis. In a similar mechanism depicted in Fig.…”

Section: Discussionmentioning

confidence: 99%

LncRNA-MEG3 functions as ferroptotic promoter to mediate OGD combined high glucose-induced death of rat brain microvascular endothelial cells via the p53-GPX4 axis

Chen¹,

Huang²,

Xia³

et al. 2020

Preprint

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Background Individuals with diabetes are exposed to a higher risk of perioperative stroke than non-diabetics mainly due to persistent hyperglycemia. lncRNA-MEG3 (long non-coding RNA maternally expressed gene 3) has been considered as an important mediator in regulating ischemic stroke. However, the functional and regulatory roles of lncRNA-MEG3 in diabetic brain ischemic injury remain unclear. Results In this study, RBMVECs (the rat brain microvascular endothelial cells) were exposed to 6 h of OGD (oxygen and glucose deprivation), and subsequent reperfusion via incubating cells with glucose of various high concentrations for 24 h to imitate in vitro diabetic brain ischemic injury. It was shown that the marker events of ferroptosis and increased lncRNA-MEG3 expression occurred after the injury induced by OGD combined with hyperglycemic treatment. However, all ferroptotic events were reversed with the treatment of MEG3-siRNA. Moreover, in this in vitro model, p53 was also characterized as a downstream target of lncRNA-MEG3. Furthermore, p53 knockdown protected RBMVECs against OGD + hyperglycemic reperfusion-induced ferroptosis, while the overexpression of p53 exerted opposite effects, implying that p53 served as a positive regulator of ferroptosis. Additionally, the overexpression or knockdown of p53 significantly modulated GPX4 expression in RBMVECs exposed to the injury induced by OGD combined with hyperglycemic treatment. Furthermore, GPX4 expression was suppressed again after the introduction of p53 into cells silenced by lncRNA-MEG3. Finally, ChIP assay uncovered that p53 was bound to GPX4 promoter. Conclusions Altogether, these data revealed that, by modulating GPX4 transcription and expression, the lncRNA-MEG3-p53 signaling pathway mediated the ferroptosis of RBMVECs upon injury induced by OGD combined with hyperglycemic treatment.

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Upregulation and activation of p53 by erastin‑induced reactive oxygen species contribute to cytotoxic and cytostatic effects in A549 lung cancer cells

Cited by 67 publications

References 22 publications

Dynasore Blocks Ferroptosis through Combined Modulation of Iron Uptake and Inhibition of Mitochondrial Respiration

Dynasore Blocks Ferroptosis through Combined Modulation of Iron Uptake and Inhibition of Mitochondrial Respiration

The Regulation of Ferroptosis by Tumor Suppressor p53 and its Pathway

LncRNA-MEG3 functions as ferroptotic promoter to mediate OGD combined high glucose-induced death of rat brain microvascular endothelial cells via the p53-GPX4 axis

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