Ferroptosis, a new form of cell death, and its relationships with tumourous diseases

Yu, Haitao; Guo, Pengyi; Xie, Xiaozai; Wang, Yi; Chen, Gang

doi:10.1111/jcmm.13008

Cited by 521 publications

(421 citation statements)

References 93 publications

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“…Thus, E− embryos experience dysregulation of energy metabolism, a phenomenon that is a major driver of cellular dysfunction and death as an ultimate consequence of VitE deficiency. Potentially, ferroptosis, a mechanism of programmed cell death due to increased lipid peroxidation [40,41], which is dependent on GPx4 and GSH, as well as VitE to prevent cell death [7], is responsible for the embryonic lethality. Notably, VitE has been suggested to function as a lipoxygenase inhibitor and thus preventing the generation of oxidized arachidonic and adrenic PE, which have been identified as lipid signaling molecules for ferroptosis [42].…”

Section: Resultsmentioning

confidence: 99%

Lethal dysregulation of energy metabolism during embryonic vitamin E deficiency

McDougall

Choi

Kim

et al. 2017

Free Radical Biology and Medicine

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Vitamin E (α-tocopherol, VitE) was discovered in 1922 for its role in preventing embryonic mortality. We investigated the underlying mechanisms causing lethality using targeted metabolomics analyses of zebrafish VitE-deficient embryos over five days of development, which coincided with their increased morbidity and mortality. VitE deficiency resulted in peroxidation of docosahexaenoic acid (DHA), depleting DHA-containing phospholipids, especially phosphatidylcholine, which also caused choline depletion. This increased lipid peroxidation also increased NADPH oxidation, which depleted glucose by shunting it to the pentose phosphate pathway. VitE deficiency was associated with mitochondrial dysfunction with concomitant impairment of energy homeostasis. The observed morbidity and mortality outcomes could be attenuated, but not fully reversed, by glucose injection into VitE-deficient embryos at developmental day one. Thus, embryonic VitE deficiency in vertebrates leads to a metabolic reprogramming that adversely affects methyl donor status and cellular energy homeostasis with lethal outcomes.

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Section: Resultsmentioning

confidence: 99%

Lethal dysregulation of energy metabolism during embryonic vitamin E deficiency

McDougall

Choi

Kim

et al. 2017

Free Radical Biology and Medicine

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“…Obviously, GPX4 protects cells from oxidative stress, and knockdown of GPX4 indeed induces ROS accumulation and subsequent ferroptosis . Unlike erastin and sorafenib, RSL3, a class 2 ferroptosis inducer, directly binds and inactivates GPX4 without influencing GSH levels . Therefore, many studies consider GPX4 to be the principal target in ferroptosis regardless of the upstream genes .…”

Section: Discussionmentioning

confidence: 99%

Sigma‐1 receptor protects against ferroptosis in hepatocellular carcinoma cells

Bai

Lei

Zhou

et al. 2019

J Cellular Molecular Medi

119

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Sigma‐1 receptor (S1R) regulates reactive oxygen species (ROS) accumulation via nuclear factor erythroid 2‐related factor 2 (NRF2), which plays a vital role in ferroptosis. Sorafenib is a strong inducer of ferroptosis but not of apoptosis. However, the mechanism of sorafenib‐induced ferroptosis in hepatocellular carcinoma (HCC) remains unclear. In this study, we found for the first time that sorafenib induced most of S1Rs away from nucleus compared to control groups in Huh‐7 cells, and ferrostatin‐1 completely blocked the translocation. S1R protein expression, but not mRNA expression, in HCC cells was significantly up‐regulated by sorafenib. Knockdown of NRF2, but not of p53 or hypoxia‐inducible factor 1‐alpha (HIF1α), markedly induced S1R mRNA expression in HCC cells. Inhibition of S1R (by RNAi or antagonists) increased sorafenib‐induced HCC cell death in vitro and in vivo. Knockdown of S1R blocked the expression of glutathione peroxidase 4 (GPX4), one of the core targets of ferroptosis, in vitro and in vivo. Iron metabolism and lipid peroxidation increased in the S1R knockdown groups treated with sorafenib compared to the control counterpart. Ferritin heavy chain 1 (FTH1) and transferrin receotor protein 1 (TFR1), both of which are critical for iron metabolism, were markedly up‐regulated in HCC cells treated with erastin and sorafenib, whereas knockdown of S1R inhibited these increases. In conclusion, we demonstrate that S1R protects HCC cells against sorafenib and subsequent ferroptosis. A better understanding of the role of S1R in ferroptosis may provide novel insight into this biological process.

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“…Kinase Akt regulates many processes like cell proliferation, apoptosis, glucose metabolism, skeletal muscle atrophy, and many others, and iron directly or indirectly can be involved in all of them . For example, iron is essential for DNA synthesis, oxidation processes, or may regulate cell death through ferroptosis . Akt activity decrease under the conditions of oxidative stress and subsequent activation of FOXO3a transcriptional factors is considered to induce an adaptive response by up‐regulation of catalase, SOD1, and other genes.…”

Section: Discussionmentioning

confidence: 99%

hmSOD1 gene mutation‐induced disturbance in iron metabolism is mediated by impairment of Akt signalling pathway

Halon-Golabek

Borkowska

Kaczor

et al. 2018

J cachexia sarcopenia muscle

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BackgroundRecently, skeletal muscle atrophy, impairment of iron metabolism, and insulin signalling have been reported in rats suffering from amyotrophic lateral sclerosis (ALS). However, the interrelationship between these changes has not been studied. We hypothesize that an impaired Akt–FOXO3a signalling pathway triggers changes in the iron metabolism in the muscles of transgenic animals.MethodsIn the present study, we used transgenic rats bearing the G93A hmSOD1 gene and their non‐transgenic littermates. The study was performed on the muscles taken from animals at three different stages of the disease: asymptomatic (ALS I), the onset of the disease (ALS II), and the terminal stage of the disease (ALS III). In order to study the molecular mechanism of changes in iron metabolism, we used SH‐SY5Y and C2C12 cell lines stably transfected with pcDNA3.1, SOD1 WT and SOD1 G93A, or FOXO3a TM‐ER.ResultsA significant decrease in P‐Akt level and changes in iron metabolism were observed even in the group of ALS I animals. This was accompanied by an increase in the active form of FOXO3a, up‐regulation of atrogin‐1, and catalase. However, significant muscle atrophy was observed in ALS II animals. An increase in ferritin L and H was accompanied by a rise in PCBP1 and APP protein levels. In SH‐SY5Y cells stably expressing SOD1 or SOD1 G93A, we observed elevated levels of ferritin L and H and non‐haem iron. Interestingly, insulin treatment significantly down‐regulated ferritin L and H proteins in the cell. Conversely, cells transfected with small interfering RNA against Akt 1, 2, 3, respectively, showed a significant increase in the ferritin and FOXO3a levels. In order to assess the role of FOXO3a in the ferritin expression, we constructed a line of SH‐SY5Y cells that expressed a fusion protein made of FOXO3a fused at the C‐terminus with the ligand‐binding domain of the oestrogen receptor (TM‐ER) being activated by 4‐hydroxytamoxifen. Treatment of the cells with 4‐hydroxytamoxifen significantly up‐regulated ferritin L and H proteins level.ConclusionsOur data suggest that impairment of insulin signalling and iron metabolism in the skeletal muscle precedes muscle atrophy and is mediated by changes in Akt/FOXO3a signalling pathways.

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Ferroptosis, a new form of cell death, and its relationships with tumourous diseases

Cited by 521 publications

References 93 publications

Lethal dysregulation of energy metabolism during embryonic vitamin E deficiency

Lethal dysregulation of energy metabolism during embryonic vitamin E deficiency

Sigma‐1 receptor protects against ferroptosis in hepatocellular carcinoma cells

hmSOD1 gene mutation‐induced disturbance in iron metabolism is mediated by impairment of Akt signalling pathway

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