RESUMO
Iron catalyses the oxidation of lipids in biological membranes and promotes a form of cell death referred to as ferroptosis1-3. Identifying where this chemistry takes place in the cell can inform the design of drugs capable of inducing or inhibiting ferroptosis in various disease-relevant settings. Whereas genetic approaches have revealed underlying mechanisms of lipid peroxide detoxification1,4,5, small molecules can provide unparalleled spatiotemporal control of the chemistry at work6. Here, we show that the ferroptosis inhibitor liproxstatin-1 (Lip-1) exerts a protective activity by inactivating iron in lysosomes. Based on this, we designed the bifunctional compound fentomycin that targets phospholipids at the plasma membrane and activates iron in lysosomes upon endocytosis, promoting oxidative degradation of phospholipids and ferroptosis. Fentomycin effectively kills primary sarcoma and pancreatic ductal adenocarcinoma cells. It acts as a lipolysis-targeting chimera (LIPTAC), preferentially targeting iron-rich CD44high cell-subpopulations7,8 associated with the metastatic disease and drug resistance9,10. Furthermore, we demonstrate that fentomycin also depletes CD44high cells in vivo and reduces intranodal tumour growth in an immunocompetent murine model of breast cancer metastasis. These data demonstrate that lysosomal iron triggers ferroptosis and that lysosomal iron redox chemistry can be exploited for therapeutic benefits.
RESUMO
Inflammation is a complex physiological process triggered in response to harmful stimuli1. It involves cells of the immune system capable of clearing sources of injury and damaged tissues. Excessive inflammation can occur as a result of infection and is a hallmark of several diseases2-4. The molecular bases underlying inflammatory responses are not fully understood. Here we show that the cell surface glycoprotein CD44, which marks the acquisition of distinct cell phenotypes in the context of development, immunity and cancer progression, mediates the uptake of metals including copper. We identify a pool of chemically reactive copper(II) in mitochondria of inflammatory macrophages that catalyses NAD(H) redox cycling by activating hydrogen peroxide. Maintenance of NAD+ enables metabolic and epigenetic programming towards the inflammatory state. Targeting mitochondrial copper(II) with supformin (LCC-12), a rationally designed dimer of metformin, induces a reduction of the NAD(H) pool, leading to metabolic and epigenetic states that oppose macrophage activation. LCC-12 interferes with cell plasticity in other settings and reduces inflammation in mouse models of bacterial and viral infections. Our work highlights the central role of copper as a regulator of cell plasticity and unveils a therapeutic strategy based on metabolic reprogramming and the control of epigenetic cell states.
Assuntos
Plasticidade Celular , Cobre , Inflamação , Transdução de Sinais , Animais , Camundongos , Cobre/metabolismo , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , NAD/metabolismo , Transdução de Sinais/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Peróxido de Hidrogênio/metabolismo , Epigênese Genética/efeitos dos fármacos , Metformina/análogos & derivados , Oxirredução , Plasticidade Celular/efeitos dos fármacos , Plasticidade Celular/genética , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/genéticaRESUMO
This symposium is the third PSL (Paris Sciences & Lettres) Chemical Biology meeting (2016, 2019, 2023) held at Institut Curie. This initiative originally started at Institut de Chimie des Substances Naturelles (ICSN) in Gif-sur-Yvette (2013, 2014), under the directorship of Professor Max Malacria, with a strong focus on chemistry. It was then continued at the Institut Curie (2015) covering a larger scope, before becoming the official PSL Chemical Biology meeting. This latest edition was postponed twice for the reasons that we know. This has given us the opportunity to invite additional speakers of great standing. This year, Institut Curie hosted around 300 participants, including 220 on site and over 80 online. The pandemic has had, at least, the virtue of promoting online meetings, which we came to realize is not perfect but has its own merits. In particular, it enables those with restricted time and resources to take part in events and meetings, which can now accommodate unlimited participants. We apologize to all those who could not attend in person this time due to space limitation at Institut Curie.
Assuntos
Biologia , Humanos , ParisRESUMO
N biogeochemical flows and associated N losses exceed currently planetary boundaries and represent a major threat for sustainability. Measuring N losses is a resource-intensive endeavour, and not suitable for ex-ante assessments, thus modelling is a common approach for estimating N losses associated with agricultural scenarios (systems, practices, situations). The aim of this study is to review some of the N models commonly used for estimating direct field emissions of agricultural systems, and to assess their suitability to systems featuring contrasted agricultural and pedoclimatic conditions. Simple N models were chosen based on their frequent use in LCA, including ecoinvent v3, Indigo-N v1/v2, AGRIBALYSE v1.2/v1.3, and the Mineral fertiliser equivalents (MFE) calculator. Model sets were contrasted, among them and with the dynamic crop model STICS, regarding their consideration of the biophysical processes determining N losses to the environment from agriculture, namely plant uptake, nitrification, denitrification, NH3 volatilisation, NO3 leaching, erosion and run-off, and N2O emission to air; using four reference agricultural datasets. Models' consideration of management drivers such as crop rotations and the allocation of fertilisers and emissions among crops in a crop rotation, over-fertilisation and fertilisation technique, were also contrasted, as well as their management of the mineralisation of soil organic matter and organic fertilisers, and of drainage regimes. For the four agricultural datasets, the ecoinvent model predicted significantly lower values for NH3 than AGRIBALYSE and STICS. For N2O, no significant differences were found among models. For NO3, ecoinvent and AGRIBALYSE predicted significantly higher emissions than STICS, regardless of the fertilisation regime. For both emissions, values of Indigo-N were close to those of STICS. By analysing the reasons for such differences, and the underlying factors considered by models, a list of recommendations was produced regarding more accurate ways to model N losses (e.g. by including the main drivers regulating emissions).
Assuntos
Agricultura , Nitrogênio , Produtos Agrícolas , Fertilizantes/análise , Nitrogênio/análise , Óxido Nitroso , SoloRESUMO
Ferroptosis is a dedicated mode of cell death involving iron, reactive oxygen species and lipid peroxidation. Involved in processes such as glutathione metabolism, lysosomal iron retention or interference with lipid metabolism, leading either to activation or inhibition of ferroptosis. Given the implications of ferroptosis in diseases such as cancer, aging, Alzheimer and infectious diseases, new molecular mechanisms underlying ferroptosis and small molecules regulators that target those mechanisms have prompted a great deal of interest. Here, we discuss the current scenario of small molecules modulating ferroptosis and critically assess what is known about their mechanisms of action.
Assuntos
Ferroptose , Morte Celular , Humanos , Ferro , Peroxidação de Lipídeos , Espécies Reativas de OxigênioRESUMO
The application of organic fertilizers (OF) can supply carbon (C) to the soil in crop fields. OF-derived C (OF-C) is often estimated using the differential method that can be biased due to indirect effects of OF on soil C. This study tested three methods to quantify OF-C: (i) the widespread differential method, (ii) the synchronic isotope method comparing plots with and without OF and (iii) the asynchronic isotope method mimicking a trial without a control plot. These methods were implemented on an Arenosol and an Andosol supplied during 13 years with slurry or compost. The results highlighted the relevance of using the synchronic isotope method, which focuses on the direct effect of OFs on the soil organic matter (without bias of vegetation change) and considers control soil's evolution. The higher the isotopic difference between soil and OF, the shorter the method implementation time needed: for an initial difference of 7.5 and 3.5 , quantification is suitable after 4 and 9 years of fertilization respectively. Attention should be paid to OF-δ13C variability to guarantee the method validity. The method proved to be suitable to study the factors controlling the OF-C fate in tropical soils.
Assuntos
Fertilizantes , Solo , Agricultura , Carbono , Isótopos de Carbono , Fertilizantes/análise , IsótoposRESUMO
CD44 is a transmembrane glycoprotein linked to various biological processes reliant on epigenetic plasticity, which include development, inflammation, immune responses, wound healing and cancer progression. Although it is often referred to as a cell surface marker, the functional regulatory roles of CD44 remain elusive. Here we report the discovery that CD44 mediates the endocytosis of iron-bound hyaluronates in tumorigenic cell lines, primary cancer cells and tumours. This glycan-mediated iron endocytosis mechanism is enhanced during epithelial-mesenchymal transitions, in which iron operates as a metal catalyst to demethylate repressive histone marks that govern the expression of mesenchymal genes. CD44 itself is transcriptionally regulated by nuclear iron through a positive feedback loop, which is in contrast to the negative regulation of the transferrin receptor by excess iron. Finally, we show that epigenetic plasticity can be altered by interfering with iron homeostasis using small molecules. This study reveals an alternative iron-uptake mechanism that prevails in the mesenchymal state of cells, which illuminates a central role of iron as a rate-limiting regulator of epigenetic plasticity.
Assuntos
Endocitose , Epigênese Genética , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/metabolismo , Ferro/metabolismo , HumanosRESUMO
Cancer stem cells (CSC) constitute a cell subpopulation in solid tumors that is responsible for resistance to conventional chemotherapy, metastasis and cancer relapse. The natural product Salinomycin can selectively target this cell niche by directly interacting with lysosomal iron, taking advantage of upregulated iron homeostasis in CSC. Here, inhibitors of the divalent metal transporterâ 1 (DMT1) have been identified that selectively target CSC by blocking lysosomal iron translocation. This leads to lysosomal iron accumulation, production of reactive oxygen species and cell death with features of ferroptosis. DMT1 inhibitors selectively target CSC in primary cancer cells and circulating tumor cells, demonstrating the physiological relevance of this strategy. Taken together, this opens up opportunities to tackle unmet needs in anti-cancer therapy.
Assuntos
Proteínas de Transporte de Cátions/química , Ferro/química , Lisossomos/química , Células-Tronco Neoplásicas/química , Piranos/química , Espécies Reativas de Oxigênio/química , Proteínas de Transporte de Cátions/metabolismo , Morte Celular , Homeostase , Humanos , Ferro/metabolismo , Lisossomos/metabolismo , Células-Tronco Neoplásicas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Regulação para CimaRESUMO
Salinomycin (1) exhibits a large spectrum of biological activities including the capacity to selectively eradicate cancer stem cells (CSC), making it and its derivatives promising candidates for the development of drug leads against CSC. It has been previously shown that salinomycin and its C20-propargylamine derivative (Ironomycin (2)) accumulate in lysosomes and sequester iron in this organelle. Herein, a library of salinomycin derivatives is reported, including products of C20-amination, C1-esterification, C9-oxidation, and C28-dehydration. The biological activity of these compounds is evaluated against transformed human mammary epithelial HMLER CD24low /CD44high cells, a well-established model of breast CSC, and HMLER CD24high /CD44low cells deprived of CSC properties. Unlike other structural alterations, derivative 4, which displays a cyclopropylamine at position C20, showed a strikingly low IC50 value of 23â nm against HMLER CD24low /CD44high cells. This study provides highly selective molecules to target the CSC niche, a potential interesting advance for drug development to prevent cancer resistance.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Receptores de Hialuronatos/química , Ferro/agonistas , Lisossomos/química , Células-Tronco Neoplásicas/química , Piranos/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Humanos , Receptores de Hialuronatos/metabolismo , Lisossomos/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Piranos/químicaRESUMO
Glucokinase phosphorylated a series of C-1 fluorinated α-d-gluco-heptuloses. These phosphorylated products were discovered to be inhibitors of α-phosphomannomutase/phosphoglucomutase (αPMM/PGM) and ß-phosphoglucomutase (ßPGM). Inhibition potency with both mutases inversely correlated to the degree of fluorination. Structural analysis with αPMM demonstrated the inhibitor binding to the active site, with the phosphate in the phosphate binding site and the anomeric hydroxyl directed to the catalytic site.
RESUMO
The clinically approved drug metformin has been shown to selectively kill persister cancer cells through mechanisms that are not fully understood. To provide further mechanistic insights, we developed a drug surrogate that phenocopies metformin and can be labeled in situ by means of click chemistry. Firstly, we found this molecule to be more potent than metformin in several cancer cell models. Secondly, this technology enabled us to provide visual evidence of mitochondrial targeting with this class of drugs. A combination of fluorescence microscopy and cyclic voltammetry indicated that metformin targets mitochondrial copper, inducing the production of reactive oxygen species in this organelle, mitochondrial dysfunction and apoptosis. Importantly, this study revealed that mitochondrial copper is required for the maintenance of a mesenchymal state of human cancer cells, and that metformin can block the epithelial-to-mesenchymal transition, a biological process that normally accounts for the genesis of persister cancer cells, through direct copper targeting.
Assuntos
Antineoplásicos/farmacologia , Cobre/metabolismo , Metformina/farmacologia , Mitocôndrias/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Antineoplásicos/química , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Química Click , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/fisiologia , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Potencial da Membrana Mitocondrial/fisiologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Metformina/química , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neoplasias/metabolismo , Neoplasias/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
[This corrects the article DOI: 10.1371/journal.pone.0206764.].
RESUMO
The success of biofortification and phytoremediation practices, addressing Se deficiency and Se pollution issues, hinges crucially on the fate of selenium in the plant media in response to uptake, translocation and assimilation processes. We investigate the fate of selenium in root and shoot compartments after 3 and 6 weeks of experiment using a total of 128 plants grown in hydroponic solution supplied with 0.2, 2, 5, 20 and 100 mg L-1 of selenium in the form of selenite, selenate and a mixture of both species. Selenate-treated plants exhibited higher root-to-shoot Se translocation and total Se uptake than selenite-treated plants. Plants took advantage of the selenate mobility and presumably of the storage capacity of leaf vacuoles to circumvent selenium toxicity within the plant. Surprisingly, 28% of selenate was found in shoots of selenite-treated plants, questioning the ability of plants to oxidize selenite into selenate. Selenomethionine and methylated organo-selenium amounted to 30% and 8% respectively in shoots and 35% and 9% in roots of the identified Se, suggesting that selenium metabolization occurred concomitantly in root and shoot plant compartments and demonstrating that non-accumulator plants can synthesize notable quantities of precursor compound for volatilization. The present study demonstrated that non-accumulator plants can develop the same strategies as hyper-accumulator plants to limit selenium toxicity. When both selenate and selenite were supplied together, plants used selenate in a storage pathway and selenite in an assimilation pathway. Plants might thereby benefit from mixed supplies of selenite and selenate by saving enzymes and energy required for selenate reduction.
Assuntos
Hidroponia/métodos , Lolium/efeitos dos fármacos , Lolium/metabolismo , Selênio/farmacocinética , Transporte Biológico , Ácido Selênico/farmacocinética , Ácido Selenioso/farmacocinética , Selênio/metabolismo , Selênio/toxicidadeRESUMO
Selenium is both essential and toxic for mammals; the range between the two roles is narrow and not only dose-dependent but also related to the chemical species present in foodstuff. Unraveling the metabolism of Se in plants as a function of Se source may thus lead to ways to increase efficiency of fertilization procedures in selenium deficient regions. In this study, stable-isotope tracing was applied for the first time in plants to simultaneously monitor the bio-incorporation of two inorganic Se species commonly used as foodstuff enrichment sources. Occurrence and speciation of Se coming from different Se sources were investigated in root and leaf extracts of ryegrass (Lolium perenne L.), which had been co-exposed to two labeled Se species ((77)SeIV and (82)SeVI). Although the plant absorbed similar amounts of Se when supplied in the form of selenite or selenate, the results evidenced marked differences in speciation and tissues allocation. Selenite was converted into organic forms incorporated mostly into high molecular weight compounds with limited translocation to leaves, whereas selenate was highly mobile being little assimilated into organic forms. Double-spike isotopic tracer methodology makes it possible to compare the metabolism of two species-specific Se sources simultaneously in a single experiment and to analyze Se behavior in not-hyperaccumulator plants, the ICP-MS sensitivity being improved by the use of enriched isotopes.