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1.
Nat Commun ; 11(1): 6339, 2020 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-33311482

RESUMO

Ferroptosis is a more recently recognized form of cell death that relies on iron-mediated oxidative damage. Here, we evaluate the impact of high-iron diets or depletion of Gpx4, an antioxidant enzyme reported as an important ferroptosis suppressor, in the pancreas of mice with cerulean- or L-arginine-induced pancreatitis, and in an oncogenic Kras murine model of spontaneous pancreatic ductal adenocarcinoma (PDAC). We find that either high-iron diets or Gpx4 depletion promotes 8-OHG release and thus activates the TMEM173/STING-dependent DNA sensor pathway, which results in macrophage infiltration and activation during Kras-driven PDAC in mice. Consequently, the administration of liproxstatin-1 (a ferroptosis inhibitor), clophosome-mediated macrophage depletion, or pharmacological and genetic inhibition of the 8-OHG-TMEM173 pathway suppresses Kras-driven pancreatic tumorigenesis in mice. GPX4 is also a prognostic marker in patients with PDAC. These findings provide pathological and mechanistic insights into ferroptotic damage in PDAC tumorigenesis in mice.


Assuntos
Carcinogênese/metabolismo , Transformação Celular Neoplásica/metabolismo , Ferroptose/fisiologia , Proteínas de Membrana/metabolismo , Pâncreas/metabolismo , Animais , Biomarcadores Tumorais , Carcinogênese/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Morte Celular/fisiologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , DNA , Dieta , Modelos Animais de Doenças , Feminino , Ferroptose/efeitos dos fármacos , Humanos , Ferro/metabolismo , Macrófagos , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Pâncreas/patologia , Pancreatite/genética , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Quinoxalinas/farmacologia , Compostos de Espiro/farmacologia , Microambiente Tumoral
2.
Nat Cell Biol ; 22(9): 1042-1048, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32868903

RESUMO

Ferroptosis is a regulated form of necrotic cell death that is caused by the accumulation of oxidized phospholipids, leading to membrane damage and cell lysis1,2. Although other types of necrotic death such as pyroptosis and necroptosis are mediated by active mechanisms of execution3-6, ferroptosis is thought to result from the accumulation of unrepaired cell damage1. Previous studies have suggested that ferroptosis has the ability to spread through cell populations in a wave-like manner, resulting in a distinct spatiotemporal pattern of cell death7,8. Here we investigate the mechanism of ferroptosis execution and discover that ferroptotic cell rupture is mediated by plasma membrane pores, similarly to cell lysis in pyroptosis and necroptosis3,4. We further find that intercellular propagation of death occurs following treatment with some ferroptosis-inducing agents, including erastin2,9 and C' dot nanoparticles8, but not upon direct inhibition of the ferroptosis-inhibiting enzyme glutathione peroxidase 4 (GPX4)10. Propagation of a ferroptosis-inducing signal occurs upstream of cell rupture and involves the spreading of a cell swelling effect through cell populations in a lipid peroxide- and iron-dependent manner.


Assuntos
Ferroptose/fisiologia , Osmose/fisiologia , Morte Celular/fisiologia , Linhagem Celular Tumoral , Células HeLa , Humanos , Ferro/metabolismo , Células MCF-7 , Necrose/metabolismo , Necrose/patologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Células U937
3.
Life Sci ; 259: 118356, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32861798

RESUMO

Curculigoside (CUR) is natural ingredient from Curculigo orchioides Gaertn with multiple biological activities. However, whether CUR protects from ulcerative colitis (UC) and underlying mechanisms are unclear. Herein, mice challenged with dextran sulfate sodium (DSS) were established and administrated with CUR for 7 days. Then histological pathologies and ferroptosis regulators were determined in vivo. The ferroptotic IEC-6 cells were prepared to investigate the underlying mechanism of CUR. Results showed that CUR inhibited the disease activity index, histological damage and cell death in mice with colitis. We also found that ferroptosis was induced in mice with colitis, as evidenced by iron overload, GSH depletion, ROS and MDA production, accompanied by decreased expression of SOD and GPX4. CUR treatment significantly reversed these alterations of ferroptotic features in DSS-induced mice. Furthermore, similar effects of CUR on ferroptosis were observed in IEC-6 cells under the combined treatment of H2O2 and iron chloride hexahydrate. Interestingly, we found that CUR could increase the selenium sensitivity and promote GPX4 transcription level in IEC-6 cells. Knockdown of GPX4 significantly blocked the protective effects of CUR on cell death, GSH and MDA contents as well as LDH activity in ferroptotic IEC-6 cells. Taken together, these findings suggest that CUR protects against ferroptosis in UC by the induction of GPX4, which presents a potential agent for UC treatment.


Assuntos
Benzoatos/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Ferroptose/efeitos dos fármacos , Glucosídeos/uso terapêutico , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Animais , Western Blotting , Linhagem Celular , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Colo/química , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Ferro/análise , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Reação em Cadeia da Polimerase em Tempo Real
4.
Nature ; 585(7823): 113-118, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32814895

RESUMO

Cancer cells, including melanoma cells, often metastasize regionally through the lymphatic system before metastasizing systemically through the blood1-4; however, the reason for this is unclear. Here we show that melanoma cells in lymph experience less oxidative stress and form more metastases than melanoma cells in blood. Immunocompromised mice with melanomas derived from patients, and immunocompetent mice with mouse melanomas, had more melanoma cells per microlitre in tumour-draining lymph than in tumour-draining blood. Cells that metastasized through blood, but not those that metastasized through lymph, became dependent on the ferroptosis inhibitor GPX4. Cells that were pretreated with chemical ferroptosis inhibitors formed more metastases than untreated cells after intravenous, but not intralymphatic, injection. We observed multiple differences between lymph fluid and blood plasma that may contribute to decreased oxidative stress and ferroptosis in lymph, including higher levels of glutathione and oleic acid and less free iron in lymph. Oleic acid protected melanoma cells from ferroptosis in an Acsl3-dependent manner and increased their capacity to form metastatic tumours. Melanoma cells from lymph nodes were more resistant to ferroptosis and formed more metastases after intravenous injection than did melanoma cells from subcutaneous tumours. Exposure to the lymphatic environment thus protects melanoma cells from ferroptosis and increases their ability to survive during subsequent metastasis through the blood.


Assuntos
Ferroptose , Linfa/metabolismo , Melanoma/patologia , Metástase Neoplásica/patologia , Animais , Sobrevivência Celular , Coenzima A Ligases/metabolismo , Feminino , Ferroptose/efeitos dos fármacos , Glutationa/metabolismo , Humanos , Ferro/metabolismo , Masculino , Melanoma/sangue , Melanoma/metabolismo , Camundongos , Metástase Neoplásica/tratamento farmacológico , Ácido Oleico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Análise de Componente Principal
5.
Life Sci ; 257: 118050, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32634425

RESUMO

BACKGROUND AND PURPOSE: Early brain injury is an essential pathological process after subarachnoid hemorrhage (SAH), with many cell death modalities. Ferroptosis is a newly discovered regulated cell death caused by the iron-dependent accumulation of lipid peroxidation, which can be prevented by glutathione peroxidase 4 (GPX4). Our study aimed to investigate the role of GPX4 in neuronal cell death after experimental SAH. METHODS: In vivo experimental SAH was induced by injecting autologous arterial blood into the prechiasmatic cistern in male Sprague-Dawley rats. Meanwhile, the in vitro SAH model was performed with primary rat cortical neurons cultured in medium containing hemoglobin (Hb). Adenovirus was used to overexpress GPX4 before experimental SAH. GPX4 expression was detected by western blot and immunofluorescence experiments. Malondialdehyde (MDA) was measured to evaluate the level of lipid peroxidation. Nissl staining was employed to assess cell death in vivo, whereas lactate dehydrogenase (LDH) release was used to evaluate cell damage in vitro. The brain water content and neurological deficits were evaluated to determine brain injury. RESULTS: Endogenous GPX4 was mainly expressed in neurons, and its expression decreased at 24 h after experimental SAH. Overexpression of GPX4 significantly reduced lipid peroxidation and cell death in the experimental SAH models both in vivo and in vitro. Moreover, overexpression of GPX4 ameliorated brain edema and neurological deficits at 24 h after SAH. CONCLUSIONS: The decrease of GPX4 expression potentially plays an important role in ferroptosis during early brain injury after SAH. Overexpression of GPX4 has a neuroprotective effect after SAH.


Assuntos
Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/uso terapêutico , Hemorragia Subaracnóidea/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Encéfalo/metabolismo , Edema Encefálico/patologia , Lesões Encefálicas/etiologia , Morte Celular/efeitos dos fármacos , Modelos Animais de Doenças , Ferroptose/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Hemorragia Subaracnóidea/metabolismo
6.
Nat Immunol ; 21(7): 727-735, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32541831

RESUMO

Stimulator-of-interferon genes (STING) is vital for sensing cytosolic DNA and initiating innate immune responses against microbial infection and tumors. Redox homeostasis is the balance of oxidative and reducing reactions present in all living systems. Yet, how the intracellular redox state controls STING activation is unclear. Here, we show that cellular redox homeostasis maintained by glutathione peroxidase 4 (GPX4) is required for STING activation. GPX4 deficiency enhanced cellular lipid peroxidation and thus specifically inhibited the cGAS-STING pathway. Concordantly, GPX4 deficiency inhibited herpes simplex virus-1 (HSV-1)-induced innate antiviral immune responses and promoted HSV-1 replication in vivo. Mechanistically, GPX4 inactivation increased production of lipid peroxidation, which led to STING carbonylation at C88 and inhibited its trafficking from the endoplasmic reticulum (ER) to the Golgi complex. Thus, cellular stress-induced lipid peroxidation specifically attenuates the STING DNA-sensing pathway, suggesting that GPX4 facilitates STING activation by maintaining redox homeostasis of lipids.


Assuntos
Herpes Simples/imunologia , Proteínas de Membrana/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Animais , Carbolinas/farmacologia , Células Cultivadas , DNA Viral/imunologia , Modelos Animais de Doenças , Retículo Endoplasmático/metabolismo , Feminino , Fibroblastos , Complexo de Golgi/metabolismo , Células HEK293 , Herpes Simples/virologia , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/imunologia , Homeostase/imunologia , Humanos , Imunidade Inata , Peroxidação de Lipídeos/genética , Peroxidação de Lipídeos/imunologia , Macrófagos Peritoneais/citologia , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Proteínas de Membrana/imunologia , Camundongos , Camundongos Knockout , Nucleotidiltransferases/metabolismo , Oxirredução , Oximas/farmacologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/antagonistas & inibidores , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Cultura Primária de Células , Carbonilação Proteica/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Sulfonamidas/farmacologia , Células THP-1 , Replicação Viral/imunologia
7.
Nat Chem Biol ; 16(5): 497-506, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32231343

RESUMO

We recently described glutathione peroxidase 4 (GPX4) as a promising target for killing therapy-resistant cancer cells via ferroptosis. The onset of therapy resistance by multiple types of treatment results in a stable cell state marked by high levels of polyunsaturated lipids and an acquired dependency on GPX4. Unfortunately, all existing inhibitors of GPX4 act covalently via a reactive alkyl chloride moiety that confers poor selectivity and pharmacokinetic properties. Here, we report our discovery that masked nitrile-oxide electrophiles, which have not been explored previously as covalent cellular probes, undergo remarkable chemical transformations in cells and provide an effective strategy for selective targeting of GPX4. The new GPX4-inhibiting compounds we describe exhibit unexpected proteome-wide selectivity and, in some instances, vastly improved physiochemical and pharmacokinetic properties compared to existing chloroacetamide-based GPX4 inhibitors. These features make them superior tool compounds for biological interrogation of ferroptosis and constitute starting points for development of improved inhibitors of GPX4.


Assuntos
Inibidores Enzimáticos/farmacologia , Nitrilos/química , Nitrilos/farmacologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/antagonistas & inibidores , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Animais , Linhagem Celular Tumoral , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Ferroptose/efeitos dos fármacos , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Camundongos SCID , Sondas Moleculares/química , Terapia de Alvo Molecular , Óxidos/química , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/química , Pró-Fármacos/química , Ratos Wistar , Selenocisteína/química , Selenocisteína/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade
8.
Nat Commun ; 11(1): 1775, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32286299

RESUMO

The increased incidence of inflammatory bowel disease (IBD) has become a global phenomenon that could be related to adoption of a Western life-style. Westernization of dietary habits is partly characterized by enrichment with the ω-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA), which entails risk for developing IBD. Glutathione peroxidase 4 (GPX4) protects against lipid peroxidation (LPO) and cell death termed ferroptosis. We report that small intestinal epithelial cells (IECs) in Crohn's disease (CD) exhibit impaired GPX4 activity and signs of LPO. PUFAs and specifically AA trigger a cytokine response of IECs which is restricted by GPX4. While GPX4 does not control AA metabolism, cytokine production is governed by similar mechanisms as ferroptosis. A PUFA-enriched Western diet triggers focal granuloma-like neutrophilic enteritis in mice that lack one allele of Gpx4 in IECs. Our study identifies dietary PUFAs as a trigger of GPX4-restricted mucosal inflammation phenocopying aspects of human CD.


Assuntos
Doença de Crohn/metabolismo , Gorduras na Dieta/efeitos adversos , Enterite/metabolismo , Ácidos Graxos Insaturados/metabolismo , Inflamação/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Adulto , Animais , Morte Celular/genética , Morte Celular/fisiologia , Doença de Crohn/genética , Enterite/etiologia , Enterite/genética , Ácidos Graxos Insaturados/genética , Feminino , Glutationa Peroxidase/metabolismo , Humanos , Inflamação/genética , Peroxidação de Lipídeos/genética , Peroxidação de Lipídeos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética
9.
Biol Pharm Bull ; 43(3): 480-487, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32115506

RESUMO

Ferroptosis is a form of necrosis caused by iron-induced accumulation of lipid hydroperoxide, involving several molecular events, and has been implicated in Parkinson's disease. Gastrodin is a component of Gastrodia elata Blume with strong antioxidant activity. We examined whether gastrodin can prevent H2O2-induced cytotoxicity in rat glioma cell line C6. For this purpose, C6 cells were pretreated with gastrodin (1, 5, 25 µM) and then exposed to 100 µM H2O2. Results showed that pretreatment of C6 cells with gastrodin decreased H2O2-induced lactate dehydrogenase (LDH) release and cell death. Moreover, gastrodin decreased intracellular malondialdehyde (MDA) level, whereas increased glutathione peroxidase (GPX) activity and glutathione (GSH) level after H2O2 treatment. In addition, treatment of deferoxamine (DFO), ferrostatin-1, and liproxstatin-1 abolished ferroptosis induced by H2O2 or erastin pretreatment. Treatment with gastrodin attenuated H2O2-induced ferroptosis and decreased lipid reactive oxygen species (ROS) (C11-BODIPY) production in C6 cells. Moreover, gastrodin increased the protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2), GPX4, ferroportin-1 (FPN1), and heme oxygenase-1 (HO-1) in C6 cells treated with H2O2. RSL3, a GPX4 inhibitor, inhibited GPX4 protein level in cells co-treated with gastrodin and 100 µM H2O2. These findings indicate that gastrodin can inhibit H2O2-induced ferroptosis through its antioxidative effect in C6 cells.


Assuntos
Antioxidantes/farmacologia , Álcoois Benzílicos/farmacologia , Ferroptose/efeitos dos fármacos , Glucosídeos/farmacologia , Peróxido de Hidrogênio/farmacologia , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo
10.
Biomed Res Int ; 2020: 6097516, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32185211

RESUMO

We here investigated the impact of mechanical ventilation (MV) time on ferroptosis in a rat renal ischemia/reperfusion injury (IRI) model. Thirty-two male adult Sprague Dawley rats were divided into four groups (n = 8/group): the sham group, IRI group, IRI+MV-4 h group, and IRI+MV-12 h group. Rats in the IRI group were subjected to 45 min bilateral renal ischemia. Rats in the IRI+MV groups were additionally mechanically ventilated with tracheal intubation after 45 min bilateral renal ischemia. Morphological changes associated with kidney injury and ferroptosis were assessed by hematoxylin and eosin staining and electron microscopy. Levels of the central regulator of ferroptosis, glutathione peroxidase 4 (GPX4), and lipid peroxidation markers 4-hydroxynonenal (4HNE) and superoxide dismutase 2 (SOD2) were determined in the kidney tissue by western blotting. Glutathione (GSH) levels were assessed in the serum and kidney homogenate. Scr levels in the IRI+MV-12 h group were significantly higher than those in the sham, IRI, and IRI+MV-4 h groups (all P < 0.001). Electron microscopy revealed the most pronouncedly abnormal mitochondrial morphology, suggestive of ferroptosis, in the IRI+MV-12 h group. The GPX4 and SOD2 protein levels progressively decreased in the following order: sham group > IRI group > IRI+MV-4 h group > IRI+MV-12 h group (P < 0.05 for all comparisons). By contrast, the 4HNE levels progressively increased in the kidney, with the highest values in the IRI+MV-12 h group (P < 0.05, vs. the IRI group and vs. the IRI+MV-4 h group). Further, the GSH levels in the serum and kidney homogenates were significantly reduced in the IRI+MV-12 h group (P < 0.01, vs. IRI group and vs. the IRI+MV-4 h group). A significant positive correlation was observed between the serum and kidney GSH levels (r 2 = 0.542, P = 0.03). These observations suggested that prolonged MV may exacerbate renal function failure, already initiated by IRI, by ferroptosis. Depletion of GSH may contribute to this effect, which requires further investigation.


Assuntos
Ferroptose/fisiologia , Rim/fisiopatologia , Traumatismo por Reperfusão/fisiopatologia , Animais , Biomarcadores/metabolismo , Glutationa/metabolismo , Rim/metabolismo , Masculino , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Ratos , Ratos Sprague-Dawley , Insuficiência Renal/metabolismo , Insuficiência Renal/fisiopatologia , Traumatismo por Reperfusão/metabolismo , Respiração Artificial/métodos , Superóxido Dismutase/metabolismo
11.
Cell Mol Biol Lett ; 25: 10, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32161620

RESUMO

Background: Ferroptosis is a newly recognized type of cell death, which is different from traditional necrosis, apoptosis or autophagic cell death. However, the position of ferroptosis in lipopolysaccharide (LPS)-induced acute lung injury (ALI) has not been explored intensively so far. In this study, we mainly analyzed the relationship between ferroptosis and LPS-induced ALI. Methods: In this study, a human bronchial epithelial cell line, BEAS-2B, was treated with LPS and ferrostatin-1 (Fer-1, ferroptosis inhibitor). The cell viability was measured using CCK-8. Additionally, the levels of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and iron, as well as the protein level of SLC7A11 and GPX4, were measured in different groups. To further confirm the in vitro results, an ALI model was induced by LPS in mice, and the therapeutic action of Fer-1 and ferroptosis level in lung tissues were evaluated. Results: The cell viability of BEAS-2B was down-regulated by LPS treatment, together with the ferroptosis markers SLC7A11 and GPX4, while the levels of MDA, 4-HNE and total iron were increased by LPS treatment in a dose-dependent manner, which could be rescued by Fer-1. The results of the in vivo experiment also indicated that Fer-1 exerted therapeutic action against LPS-induced ALI, and down-regulated the ferroptosis level in lung tissues. Conclusions: Our study indicated that ferroptosis has an important role in the progression of LPS-induced ALI, and ferroptosis may become a novel target in the treatment of ALI patients.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Cicloexilaminas/uso terapêutico , Ferroptose/efeitos dos fármacos , Fenilenodiaminas/uso terapêutico , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/patologia , Aldeídos/metabolismo , Sistema y+ de Transporte de Aminoácidos/metabolismo , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cicloexilaminas/farmacologia , Ferroptose/imunologia , Humanos , Ferro/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fenilenodiaminas/farmacologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo
12.
Sci Rep ; 10(1): 2268, 2020 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-32042051

RESUMO

The intracellular levels of the cytoprotective enzyme heme oxygenase-1 (HO-1) are tightly controlled. Here, we reveal a novel mechanism preventing the exaggerated expression of HO-1. The analysis of mice with a knock-out in the ubiquitin E3 ligase seven in absentia homolog 2 (SIAH2) showed elevated HO-1 protein levels in specific organs such as heart, kidney and skeletal muscle. Increased HO-1 protein amounts were also seen in human cells deleted for the SIAH2 gene. The higher HO-1 levels are not only due to an increased protein stability but also to elevated expression of the HO-1 encoding HMOX1 gene, which depends on the transcription factor nuclear factor E2-related factor 2 (NRF2), a known SIAH2 target. Dependent on its RING (really interesting new gene) domain, expression of SIAH2 mediates proteasome-dependent degradation of its interaction partner HO-1. Additionally SIAH2-deficient cells are also characterized by reduced expression levels of glutathione peroxidase 4 (GPX4), rendering the knock-out cells more sensitive to ferroptosis.


Assuntos
Heme Oxigenase-1/metabolismo , Proteínas de Membrana/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Nucleares/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Sistemas CRISPR-Cas/genética , Regulação para Baixo , Ferroptose , Fibroblastos , Técnicas de Silenciamento de Genes , Células HEK293 , Heme Oxigenase-1/genética , Humanos , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Proteínas Nucleares/genética , Oxigênio/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Cultura Primária de Células , Complexo de Endopeptidases do Proteassoma/metabolismo , Domínios Proteicos , Estabilidade Proteica , Proteólise , Ubiquitina-Proteína Ligases/genética , Ubiquitinação
13.
Cell Prolif ; 53(3): e12761, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32100402

RESUMO

Ferroptosis is a recently defined, non-apoptotic, regulated cell death (RCD) process that comprises abnormal metabolism of cellular lipid oxides catalysed by iron ions or iron-containing enzymes. In this process, a variety of inducers destroy the cell redox balance and produce a large number of lipid peroxidation products, eventually triggering cell death. However, in terms of morphology, biochemistry and genetics, ferroptosis is quite different from apoptosis, necrosis, autophagy-dependent cell death and other RCD processes. A growing number of studies suggest that the relationship between ferroptosis and cancer is extremely complicated and that ferroptosis promises to be a novel approach for the cancer treatment. This article primarily focuses on the mechanism of ferroptosis and discusses the potential application of ferroptosis in cancer therapy.


Assuntos
Ferroptose , Peroxidação de Lipídeos , Neoplasias/metabolismo , Peróxidos/metabolismo , Animais , Glutationa/metabolismo , Humanos , Ferro/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteína Supressora de Tumor p53/metabolismo
14.
Biochim Biophys Acta Gen Subj ; 1864(4): 129539, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31958545

RESUMO

BACKGROUND: Cancer is one of the major threats to human health and current cancer therapies have been unsuccessful in eradicating it. Ferroptosis is characterized by iron-dependence and lipid hydroperoxides accumulation, and its primary mechanism involves the suppression of system Xc--GSH (glutathione)-GPX4 (glutathione peroxidase 4) axis. Co-incidentally, cancer cells are also metabolically characterized by iron addiction and ROS tolerance, which makes them vulnerable to ferroptosis. This may provide a new tactic for cancer therapy. SCOPE OF REVIEW: The general features and mechanisms of ferroptosis, and the basis that makes cancer cells vulnerable to ferroptosis are described. Further, we emphatically discussed that disrupting GSH may not be ideal for triggering ferroptosis of cancer cells in vivo, but directly inhibiting GPX4 and its compensatory members could be more effective. Finally, the various approaches to directly inhibit GPX4 without disturbing GSH were described. MAJOR CONCLUSIONS: Targeting system Xc- or GSH may not effectively trigger cancer cells' ferroptosis in vivo the existence of other compensatory pathways. However, directly targeting GPX4 and its compensatory members without disrupting GSH may be more effective to induce ferroptosis in cancer cells in vivo, as GPX4 is essential in preventing ferroptosis. GENERAL SIGNIFICANCE: Cancer is a severe threat to human health. Ferroptosis-based cancer therapy strategies are promising, but how to effectively induce ferroptosis in cancer cells in vivo is still a question without clear answers. Thus, the viewpoints raised in this review may provide some references and different perspectives for researchers working on ferroptosis-based cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Ferroptose/efeitos dos fármacos , Glutationa/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/antagonistas & inibidores , Animais , Ensaios de Seleção de Medicamentos Antitumorais , Glutationa/metabolismo , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Espécies Reativas de Oxigênio/metabolismo
15.
Molecules ; 25(1)2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31906464

RESUMO

Ginsenosides are active components found abundantly in ginseng which has been used as a medicinal herb to modify disease status for thousands of years. However, the pharmacological activity of ginsenoside Re in the neuronal system remains to be elucidated. Neuroprotective activity of ginsenoside Re was investigated in SH-SY5Y cells exposed to 6-hydroxydopamine (6-OHDA) to induce cellular injury. Ginsenoside Re significantly inhibited 6-OHDA-triggered cellular damage as judged by analysis of tetrazolium dye reduction and lactose dehydrogenase release. In addition, ginsenoside Re induced the expression of the antioxidant protein glutathione peroxidase 4 (GPX4) but not catalase, glutathione peroxidase 1, glutathione reductase, or superoxide dismutase-1. Furthermore, upregulation of GPX4 by ginsenoside Re was mediated by phosphoinositide 3-kinase and extracellular signal-regulated kinase but not by p38 mitogen-activated protein kinase or c-Jun N-terminal kinase. Ginsenoside Re also suppressed 6-OHDA-triggered cellular accumulation of reactive oxygen species and peroxidation of membrane lipids. The GPX4 inhibitor (1S,3R)-RSL3 reversed ginsenoside Re-mediated inhibition of cellular damage in SH-SY5Y cells exposed to 6-OHDA, indicating that the neuronal activity of ginsenoside Re is due to upregulation of GPX4. These findings suggest that ginsenoside Re-dependent upregulation of GPX4 reduces oxidative stress and thereby alleviates 6-OHDA-induced neuronal damage.


Assuntos
Ginsenosídeos/farmacologia , Oxidopamina/farmacologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Catalase/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Glutationa Peroxidase/metabolismo , Glutationa Redutase/metabolismo , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase-1/metabolismo
16.
Cell Death Dis ; 11(1): 51, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31974344

RESUMO

Decreased expression of mitochondrial frataxin (FXN) causes Friedreich's ataxia (FRDA), a neurodegenerative disease with type 2 diabetes (T2D) as severe comorbidity. Brown adipose tissue (BAT) is a mitochondria-enriched and anti-diabetic tissue that turns excess energy into heat to maintain metabolic homeostasis. Here we report that the FXN knock-in/knock-out (KIKO) mouse shows hyperlipidemia, reduced energy expenditure and insulin sensitivity, and elevated plasma leptin, recapitulating T2D-like signatures. FXN deficiency leads to disrupted mitochondrial ultrastructure and oxygen consumption as well as lipid accumulation in BAT. Transcriptomic data highlights cold intolerance in association with iron-mediated cell death (ferroptosis). Impaired PKA-mediated lipolysis and expression of genes controlling mitochondrial metabolism, lipid catabolism and adipogenesis were observed in BAT of KIKO mice as well as in FXN-deficient T37i brown and primary adipocytes. Significant susceptibility to ferroptosis was observed in adipocyte precursors that showed increased lipid peroxidation and decreased glutathione peroxidase 4. Collectively our data point to BAT dysfunction in FRDA and suggest BAT as promising therapeutic target to overcome T2D in FRDA.


Assuntos
Tecido Adiposo Marrom/metabolismo , Ataxia de Friedreich/metabolismo , Proteínas de Ligação ao Ferro/metabolismo , Metabolismo dos Lipídeos , Mitocôndrias/metabolismo , Termogênese/genética , Adipócitos/metabolismo , Tecido Adiposo Marrom/ultraestrutura , Animais , Temperatura Baixa , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Ferroptose/genética , Ataxia de Friedreich/genética , Hiperlipidemias/genética , Hiperlipidemias/metabolismo , Resistência à Insulina/genética , Proteínas de Ligação ao Ferro/genética , Leptina/sangue , Lipólise/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Eletrônica de Transmissão , Mitocôndrias/ultraestrutura , Estresse Oxidativo/genética , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , RNA-Seq
17.
Anticancer Drugs ; 31(1): 27-34, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31490283

RESUMO

Ferroptosis is a newly discovered type of cell death decided by iron-dependent lipid peroxidation, but its role in glioblastoma cell death remains unclear. Ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID), has been associated with antitumorigenic effects in many cancers. In this study, we first found that ibuprofen inhibited the viabilities of glioblastoma cells in vitro and in vivo, accompanied by abnormal increase in intracellular lipid peroxidation. Further study showed that the cell growth inhibition caused by ibuprofen could be rescued by the ferroptosis inhibitors deferoxamine (DFO), ferrostatin-1 and Liproxstatin-1. Nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) are key regulators of ferroptosis. Our data showed that Nrf2, GPX4 and SLC7A11 were downregulated in glioblastoma cells under ibuprofen treatment. Interestingly, we found that decreased mRNA expression of GPX4 and SLC7A11 was accompanied with reduced Nrf2, which is a redox sensitive transcription factor that controls the expression of intracellular redox-balancing proteins such as GPX4 and SLC7A11. All the data suggested that Nrf2 could regulate the expression of GPX4 and SLC7A11 in glioma cells. Taken together, our findings reveal that ibuprofen could induce ferroptosis of glioblastoma cells via downregulation of Nrf2 signaling pathway and is a potential drug for glioma treatment.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Ferroptose/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Ibuprofeno/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Sistema y+ de Transporte de Aminoácidos/metabolismo , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Glioblastoma/metabolismo , Glioblastoma/patologia , Xenoenxertos , Humanos , Camundongos , Camundongos Nus , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Transdução de Sinais/efeitos dos fármacos
18.
FEBS Lett ; 594(4): 611-624, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31581313

RESUMO

Ras-selective lethal small molecule 3 (RSL3), a drug candidate prototype for cancer chemotherapy, triggers ferroptosis by inactivating the glutathione peroxidase glutathione peroxidase 4 (GPx4). Here, we report the purification of the protein indispensable for GPx4 inactivation by RSL3. Mass spectrometric analysis identified 14-3-3 isoforms as candidates, and recombinant human 14-3-3ε confirms the identification. The function of 14-3-3ε is redox-regulated. Moreover, overexpression or silencing of the gene coding for 14-3-3ε consistently controls the inactivation of GPx4 by RSL3. The interaction of GPx4 with a redox-regulated adaptor protein operating in cell signaling further contributes to frame it within redox-regulated pathways of cell survival and death and opens new therapeutic perspectives.


Assuntos
Proteínas 14-3-3/metabolismo , Carbolinas/farmacologia , Ferroptose/efeitos dos fármacos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Animais , Citosol/efeitos dos fármacos , Citosol/metabolismo , Ativação Enzimática/efeitos dos fármacos , Células HEK293 , Humanos , Ratos
19.
Am J Pathol ; 190(1): 68-81, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31610178

RESUMO

Oxidative stress and its associated lipid peroxidation play a key role in nonalcoholic steatohepatitis (NASH). Ferroptosis is a recently recognized type of cell death characterized by an iron-dependent and lipid peroxidation-mediated nonapoptotic cell death. We demonstrate the impact of ferroptosis on the progression of NASH induced by methionine/choline-deficient diet (MCD) feeding for 10 days. RSL-3 (a ferroptosis inducer) treatment showed decreased hepatic expression of glutathione peroxidase 4 (GPX4) and conversely increased 12/15-lipoxygenase, and apoptosis-inducing factor, indicating that ferroptosis plays a key role in NASH-related lipid peroxidation and its associated cell death. Consistently, levels of serum biochemical, hepatic steatosis, inflammation, and apoptosis in MCD-fed mice were exacerbated with RSL-3 treatment. However, MCD-fed mice treated with sodium selenite (a GPX4 activator) showed increase of hepatic GPX4, accompanied by reduced NASH severity. To chelate iron, deferoxamine mesylate salt was used. Administration of deferoxamine mesylate salt significantly reduced NASH severity and abolished the harmful effects of RSL-3 in MCD-fed mice. Finally, treatment with liproxstatin-1 (a ferroptosis inhibitor) repressed hepatic lipid peroxidation and its associated cell death, resulting in decreased NASH severity. Consistent with the in vivo findings, modulation of ferroptosis/GPX4 affected hepatocellular death in palmitic acid-induced in vitro NASH milieu. We conclude that GPX4 and its related ferroptosis might play a major role in the development of NASH.


Assuntos
Dieta/efeitos adversos , Ferroptose , Inflamação/patologia , Peroxidação de Lipídeos , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo , Animais , Apoptose , Morte Celular , Deficiência de Colina/complicações , Progressão da Doença , Inflamação/etiologia , Inflamação/metabolismo , Masculino , Metionina/deficiência , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo
20.
Dig Dis Sci ; 65(7): 1999-2008, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31701262

RESUMO

BACKGROUND: DnaJ/Hsp40 homolog, subfamily B, member 6 (DNAJB6) is significantly down-regulated in esophageal squamous cell carcinoma (ESCC), while its complicated molecular mechanisms are still unknown. AIMS: To investigate the relationship between DNAJB6 and ESCC. METHODS: The expression of DNAJB6 was detected in ESCC patient by Western blot and immunohistochemistry. To overexpress DNAJB6a by lentivirus infection, colony-forming, CCK-8, transwell, mouse xenograft assays were utilized to verify the proliferous, invasive, and migratory role of DNAJB6a in ESCC cells. The MDA and GSH assays determine whether DNAJB6a participates in cell redox reaction. The variation of AKT and GPX4 was detected by Western blot. RESULTS: The correlation between DNAJB6 level and lymph node metastasis in ESCC patient was negative. Overexpressing DNAJB6a shows tumor-suppressive effects in vitro and in vivo. In addition, DNAJB6a overexpression was accompanied together with a remarkable reduction in the protein levels of GPX4 and phosphorylated AKT (p-AKT). CONCLUSION: DNAJB6 plays an important anti-oncogenic role in ESCC evolvement via ferroptosis.


Assuntos
Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Proteínas de Choque Térmico HSP40/genética , Chaperonas Moleculares/genética , Proteínas do Tecido Nervoso/genética , Animais , Western Blotting , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Ferroptose/genética , Glutationa/metabolismo , Proteínas de Choque Térmico HSP40/metabolismo , Humanos , Técnicas In Vitro , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Mitocôndrias/ultraestrutura , Chaperonas Moleculares/metabolismo , Gradação de Tumores , Invasividade Neoplásica , Estadiamento de Neoplasias , Proteínas do Tecido Nervoso/metabolismo , Oxirredução , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Isoformas de Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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