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This corrects the article DOI: 10.1038/nature22964.
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To better understand the mechanisms at the basis of neutrophil functions during SARS-CoV-2, we studied patients with severe COVID-19 pneumonia. They had high blood proportion of degranulated neutrophils and elevated plasma levels of myeloperoxidase (MPO), elastase, and MPO-DNA complexes, which are typical markers of neutrophil extracellular traps (NET). Their neutrophils display dysfunctional mitochondria, defective oxidative burst, increased glycolysis, glycogen accumulation in the cytoplasm, and increase glycogenolysis. Hypoxia-inducible factor 1α (ΗΙF-1α) is stabilized in such cells, and it controls the level of glycogen phosphorylase L (PYGL), a key enzyme in glycogenolysis. Inhibiting PYGL abolishes the ability of neutrophils to produce NET. Patients displayed significant increases of plasma levels of molecules involved in the regulation of neutrophils' function including CCL2, CXCL10, CCL20, IL-18, IL-3, IL-6, G-CSF, GM-CSF, IFN-γ. Our data suggest that metabolic remodelling is vital for the formation of NET and for boosting neutrophil inflammatory response, thus, suggesting that modulating ΗΙF-1α or PYGL could represent a novel approach for innovative therapies.
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COVID-19/imunologia , COVID-19/metabolismo , Neutrófilos/imunologia , Neutrófilos/metabolismo , SARS-CoV-2 , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/sangue , Estudos de Casos e Controles , Estudos de Coortes , Citocinas/sangue , Armadilhas Extracelulares/imunologia , Armadilhas Extracelulares/metabolismo , Feminino , Glicogênio Fosforilase Hepática/sangue , Granulócitos/imunologia , Granulócitos/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/sangue , Masculino , Redes e Vias Metabólicas/genética , Redes e Vias Metabólicas/imunologia , Pessoa de Meia-Idade , Ativação de Neutrófilo , Peroxidase/sangue , Explosão Respiratória , Índice de Gravidade de DoençaRESUMO
Activation of the PTEN-PI3K-mTORC1 pathway consolidates metabolic programs that sustain cancer cell growth and proliferation. Here we show that mechanistic target of rapamycin complex 1 (mTORC1) regulates polyamine dynamics, a metabolic route that is essential for oncogenicity. By using integrative metabolomics in a mouse model and human biopsies of prostate cancer, we identify alterations in tumours affecting the production of decarboxylated S-adenosylmethionine (dcSAM) and polyamine synthesis. Mechanistically, this metabolic rewiring stems from mTORC1-dependent regulation of S-adenosylmethionine decarboxylase 1 (AMD1) stability. This novel molecular regulation is validated in mouse and human cancer specimens. AMD1 is upregulated in human prostate cancer with activated mTORC1. Conversely, samples from a clinical trial with the mTORC1 inhibitor everolimus exhibit a predominant decrease in AMD1 immunoreactivity that is associated with a decrease in proliferation, in line with the requirement of dcSAM production for oncogenicity. These findings provide fundamental information about the complex regulatory landscape controlled by mTORC1 to integrate and translate growth signals into an oncogenic metabolic program.
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Adenosilmetionina Descarboxilase/metabolismo , Complexos Multiproteicos/metabolismo , Poliaminas/metabolismo , Neoplasias da Próstata/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Adenosilmetionina Descarboxilase/imunologia , Animais , Proliferação de Células , Ativação Enzimática , Everolimo/uso terapêutico , Humanos , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina , Metabolômica , Camundongos , Complexos Multiproteicos/antagonistas & inibidores , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Estabilidade Proteica , S-Adenosilmetionina/análogos & derivados , S-Adenosilmetionina/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidoresRESUMO
Memory B cell responses are vital for protection against infections but must also be regulated to prevent autoimmunity. Cognate T cell help, somatic hypermutation, and affinity maturation within germinal centers (GCs) are required for high-affinity memory B cell formation; however, the signals that commit GC B cells to the memory pool remain unclear. In this study, we identify a role for IgG-immune complexes (ICs), FcγRs, and BAFF during the formation of memory B cells in mice. We found that early secretion of IgG in response to immunization with a T-dependent Ag leads to IC-FcγR interactions that induce dendritic cells to secrete BAFF, which acts at or upstream of Bcl-6 in activated B cells. Loss of CD16, hematopoietic cell-derived BAFF, or blocking IC:FcγR regions in vivo diminished the expression of Bcl-6, the frequency of GC and memory B cells, and secondary Ab responses. BAFF also contributed to the maintenance and/or expansion of the follicular helper T cell population, although it was dispensable for their formation. Thus, early Ab responses contribute to the optimal formation of B cell memory through IgG-ICs and BAFF. Our work defines a new role for FcγRs in GC and memory B cell responses.
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Complexo Antígeno-Anticorpo/imunologia , Fator Ativador de Células B/biossíntese , Imunoglobulina G/imunologia , Memória Imunológica/imunologia , Receptores de IgG/imunologia , Transferência Adotiva , Animais , Fator Ativador de Células B/genética , Linfócitos B/citologia , Linfócitos B/imunologia , Diferenciação Celular/imunologia , Células Cultivadas , Células Dendríticas/imunologia , Centro Germinativo/citologia , Centro Germinativo/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas c-bcl-6/biossíntese , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-bcl-6/imunologia , Receptores de IgG/genética , Linfócitos T Auxiliares-Indutores/imunologiaRESUMO
B cell activation leads to proliferation and Ab production that can protect from pathogens or promote autoimmunity. Regulation of cell metabolism is essential to support the demands of lymphocyte growth and effector function and may regulate tolerance. In this study, we tested the regulation and role of glucose uptake and metabolism in the proliferation and Ab production of control, anergic, and autoimmune-prone B cells. Control B cells had a balanced increase in lactate production and oxygen consumption following activation, with proportionally increased glucose transporter Glut1 expression and mitochondrial mass upon either LPS or BCR stimulation. This contrasted with metabolic reprogramming of T cells, which had lower glycolytic flux when resting but disproportionately increased this pathway upon activation. Importantly, tolerance greatly affected B cell metabolic reprogramming. Anergic B cells remained metabolically quiescent, with only a modest increase in glycolysis and oxygen consumption with LPS stimulation. B cells chronically stimulated with elevated BAFF, however, rapidly increased glycolysis and Ab production upon stimulation. Induction of glycolysis was critical for Ab production, as glycolytic inhibition with the pyruvate dehydrogenase kinase inhibitor dichloroacetate sharply suppressed B cell proliferation and Ab secretion in vitro and in vivo. Furthermore, B cell-specific deletion of Glut1 led to reduced B cell numbers and impaired Ab production in vivo. Together, these data show that activated B cells require Glut1-dependent metabolic reprogramming to support proliferation and Ab production that is distinct from T cells and that this glycolytic reprogramming is regulated in tolerance.
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Formação de Anticorpos , Fator Ativador de Células B/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Anergia Clonal/imunologia , Animais , Fator Ativador de Células B/genética , Ácido Dicloroacético/farmacologia , Glucose/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Glicólise/efeitos dos fármacos , Homeostase , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Ativação Linfocitária/imunologia , Camundongos , Camundongos Transgênicos , Mitocôndrias/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
Prostate cancer is among the most frequent cancers in men, and despite its high rate of cure, the high number of cases results in an elevated mortality worldwide. Importantly, prostate cancer incidence is dramatically increasing in western societies in the past decades, suggesting that this type of tumor is exquisitely sensitive to lifestyle changes. Prostate cancer frequently exhibits alterations in the PTEN gene (inactivating mutations or gene deletions) or at the protein level (reduced protein expression or altered sub-cellular compartmentalization). The relevance of PTEN in this type of cancer is further supported by the fact that the sole deletion of PTEN in the murine prostate epithelium recapitulates many of the features of the human disease. In order to study the molecular alterations in prostate cancer, we need to overcome the methodological challenges that this tissue imposes. In this review we present protocols and methods, using PTEN as proof of concept, to study different molecular characteristics of prostate cancer.
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PTEN Fosfo-Hidrolase/análise , PTEN Fosfo-Hidrolase/biossíntese , Neoplasias da Próstata/metabolismo , Proteínas Supressoras de Tumor/análise , Proteínas Supressoras de Tumor/biossíntese , Animais , Humanos , Masculino , Camundongos , Mutação/genética , PTEN Fosfo-Hidrolase/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Proteínas Supressoras de Tumor/genéticaRESUMO
Immunological function requires metabolic support to suit the needs of lymphocytes at a variety of distinct differentiation and activation states. It is now evident that the signaling pathways that drive lymphocyte survival and activity can directly control cellular metabolism. This linkage provides a mechanism by which activation and specific signaling pathways provide a supply of appropriate and required nutrients to support cell functions in a pro-active supply rather than consumption-based metabolic model. In this way, the metabolism and fuel choices of lymphocytes are guided to specifically match the anticipated needs. If the fuel choice or metabolic pathways of lymphocytes are dysregulated, however, metabolic checkpoints can become activated to disrupt immunological function. These changes are now shown in several immunological diseases and may open new opportunities to selectively enhance or suppress specific immune functions through targeting of glucose, lipid, or amino acid metabolism.
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Ativação Linfocitária , Linfócitos/imunologia , Linfócitos/metabolismo , Diferenciação Celular/imunologia , Glucose/metabolismo , Humanos , Linfócitos/citologia , Transdução de Sinais/imunologiaRESUMO
In response to nutrient shortage or organelle damage, cells undergo macroautophagy. Starvation of glucose, an essential nutrient, is thought to promote autophagy in mammalian cells. We thus aimed to determine the role of autophagy in cell death induced by glucose deprivation. Glucose withdrawal induces cell death that can occur by apoptosis (in Bax, Bak-deficient mouse embryonic fibroblasts or HeLa cells) or by necrosis (in Rh4 rhabdomyosarcoma cells). Inhibition of autophagy by chemical or genetic means by using 3-methyladenine, chloroquine, a dominant negative form of ATG4B or silencing Beclin-1, Atg7, or p62 indicated that macroautophagy does not protect cells undergoing necrosis or apoptosis upon glucose deprivation. Moreover, glucose deprivation did not induce autophagic flux in any of the four cell lines analyzed, even though mTOR was inhibited. Indeed, glucose deprivation inhibited basal autophagic flux. In contrast, the glycolytic inhibitor 2-deoxyglucose induced prosurvival autophagy. Further analyses indicated that in the absence of glucose, autophagic flux induced by other stimuli is inhibited. These data suggest that the role of autophagy in response to nutrient starvation should be reconsidered.
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Autofagia/fisiologia , Fibroblastos/metabolismo , Glucose/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Antimetabólitos/farmacologia , Proteínas Reguladoras de Apoptose/metabolismo , Autofagia/efeitos dos fármacos , Proteína 7 Relacionada à Autofagia , Proteínas Relacionadas à Autofagia , Proteína Beclina-1 , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Cisteína Endopeptidases/metabolismo , Desoxiglucose/farmacologia , Glucose/farmacologia , Células HeLa , Humanos , Proteínas de Membrana/metabolismo , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Proteína Sequestossoma-1 , Edulcorantes/metabolismo , Edulcorantes/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Fator de Transcrição TFIIH , Fatores de Transcrição/metabolismo , Enzimas Ativadoras de Ubiquitina/metabolismoRESUMO
In patients infected by SARS-CoV-2 who experience an exaggerated inflammation leading to pneumonia, monocytes likely play a major role but have received poor attention. Thus, we analyzed peripheral blood monocytes from patients with COVID-19 pneumonia and found that these cells show signs of altered bioenergetics and mitochondrial dysfunction, had a reduced basal and maximal respiration, reduced spare respiratory capacity, and decreased proton leak. Basal extracellular acidification rate was also diminished, suggesting reduced capability to perform aerobic glycolysis. Although COVID-19 monocytes had a reduced ability to perform oxidative burst, they were still capable of producing TNF and IFN-γ in vitro. A significantly high amount of monocytes had depolarized mitochondria and abnormal mitochondrial ultrastructure. A redistribution of monocyte subsets, with a significant expansion of intermediate/pro-inflammatory cells, and high amounts of immature monocytes were found, along with a concomitant compression of classical monocytes, and an increased expression of inhibitory checkpoints like PD-1/PD-L1. High plasma levels of several inflammatory cytokines and chemokines, including GM-CSF, IL-18, CCL2, CXCL10, and osteopontin, finally confirm the importance of monocytes in COVID-19 immunopathogenesis.
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COVID-19/patologia , Metabolismo Energético/fisiologia , Mitocôndrias/metabolismo , Monócitos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/virologia , Estudos de Casos e Controles , Quimiocinas/sangue , Citocinas/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias/ultraestrutura , Monócitos/citologia , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , SARS-CoV-2/isolamento & purificaçãoRESUMO
Gene dosage is a key defining factor to understand cancer pathogenesis and progression, which requires the development of experimental models that aid better deconstruction of the disease. Here, we model an aggressive form of prostate cancer and show the unconventional association of LKB1 dosage to prostate tumorigenesis. Whereas loss of Lkb1 alone in the murine prostate epithelium was inconsequential for tumorigenesis, its combination with an oncogenic insult, illustrated by Pten heterozygosity, elicited lethal metastatic prostate cancer. Despite the low frequency of LKB1 deletion in patients, this event was significantly enriched in lung metastasis. Modeling the role of LKB1 in cellular systems revealed that the residual activity retained in a reported kinase-dead form, LKB1K78I, was sufficient to hamper tumor aggressiveness and metastatic dissemination. Our data suggest that prostate cells can function normally with low activity of LKB1, whereas its complete absence influences prostate cancer pathogenesis and dissemination.
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Neoplasias da Próstata/enzimologia , Proteínas Serina-Treonina Quinases/genética , Quinases Proteína-Quinases Ativadas por AMP , Proteínas Quinases Ativadas por AMP , Animais , Linhagem Celular Tumoral , Progressão da Doença , Epitélio/enzimologia , Epitélio/patologia , Células HEK293 , Heterozigoto , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Nus , Proteínas Mutantes/metabolismo , Metástase Neoplásica , PTEN Fosfo-Hidrolase/metabolismo , Próstata/enzimologia , Próstata/patologia , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/metabolismoRESUMO
With the advent of OMICs technologies, both individual research groups and consortia have spear-headed the characterization of human samples of multiple pathophysiologic origins, resulting in thousands of archived genomes and transcriptomes. Although a variety of web tools are now available to extract information from OMICs data, their utility has been limited by the capacity of nonbioinformatician researchers to exploit the information. To address this problem, we have developed CANCERTOOL, a web-based interface that aims to overcome the major limitations of public transcriptomics dataset analysis for highly prevalent types of cancer (breast, prostate, lung, and colorectal). CANCERTOOL provides rapid and comprehensive visualization of gene expression data for the gene(s) of interest in well-annotated cancer datasets. This visualization is accompanied by generation of reports customized to the interest of the researcher (e.g., editable figures, detailed statistical analyses, and access to raw data for reanalysis). It also carries out gene-to-gene correlations in multiple datasets at the same time or using preset patient groups. Finally, this new tool solves the time-consuming task of performing functional enrichment analysis with gene sets of interest using up to 11 different databases at the same time. Collectively, CANCERTOOL represents a simple and freely accessible interface to interrogate well-annotated datasets and obtain publishable representations that can contribute to refinement and guidance of cancer-related investigations at all levels of hypotheses and design.Significance: In order to facilitate access of research groups without bioinformatics support to public transcriptomics data, we have developed a free online tool with an easy-to-use interface that allows researchers to obtain quality information in a readily publishable format. Cancer Res; 78(21); 6320-8. ©2018 AACR.
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Biologia Computacional/métodos , Neoplasias/genética , Algoritmos , Gráficos por Computador , Bases de Dados Factuais , Bases de Dados Genéticas , Genômica , Humanos , Internet , Oncologia , Proteômica , Software , Transcriptoma , Interface Usuário-Computador , Fluxo de TrabalhoRESUMO
Prostate cancer is diagnosed late in life, when co-morbidities are frequent. Among them, hypertension, hypercholesterolemia, diabetes or metabolic syndrome exhibit an elevated incidence. In turn, prostate cancer patients frequently undergo chronic pharmacological treatments that could alter disease initiation, progression and therapy response. Here we show that treatment with anti-cholesterolemic drugs, statins, at doses achieved in patients, enhance the pro-tumorigenic activity of obesogenic diets. In addition, the use of a mouse model of prostate cancer and human prostate cancer xenografts revealed that in vivo simvastatin administration alone increases prostate cancer aggressiveness. In vitro cell line systems supported the notion that this phenomenon occurs, at least in part, through the direct action on cancer cells of low doses of statins, in range of what is observed in human plasma. In sum, our results reveal a prostate cancer experimental system where statins exhibit an undesirable effect, and warrant further research to address the relevance and implications of this observation in human prostate cancer.
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Salp15, a salivary protein of Ixodes ticks, inhibits the activation of naïve CD4 T cells. Treatment with Salp15 results in the inhibition of early signaling events and the production of the autocrine growth factor, interleukin-2. The fate of the CD4 T cells activated in the presence of Salp15 or its long-term effects are, however, unknown. We now show that Salp15 binding to CD4 is persistent and induces a long-lasting immunomodulatory effect. The activity of Salp15 results in sustained diminished cross-antigenic antibody production even after interruption of the treatment with the protein. Transcriptionally, the salivary protein provokes an acute effect that includes known activation markers, such as Il2 or Cd44, and that fades over time. The long-term effects exerted by Salp15 do not involve the induction of either anergy traits nor increased populations of regulatory T cells. Similarly, the treatment with Salp15 does not result in B cell anergy or the generation of myeloid suppressor cells. However, Salp15 induces the increased expression of the ectoenzyme, CD73, in regulatory T cells and increased production of adenosine. Our study provides a profound characterization of the immunomodulatory activity of Salp15 and suggests that its long-term effects are due to the specific regulation of CD73.
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Tolerância Imunológica/efeitos dos fármacos , Imunomodulação/efeitos dos fármacos , Imunossupressores/farmacologia , Proteínas e Peptídeos Salivares/farmacologia , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Hematopoese/efeitos dos fármacos , Hematopoese/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Imunoglobulina G/imunologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Camundongos , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Transcrição GênicaRESUMO
This corrects the article DOI: 10.1038/ncb3357.
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Extracellular vesicles (EV) are emerging structures with promising properties for intercellular communication. In addition, the characterization of EV in biofluids is an attractive source of non-invasive diagnostic, prognostic and predictive biomarkers. Here we show that urinary EV (uEV) from prostate cancer (PCa) patients exhibit genuine and differential physical and biological properties compared to benign prostate hyperplasia (BPH). Importantly, transcriptomics characterization of uEVs led us to define the decreased abundance of Cadherin 3, type 1 (CDH3) transcript in uEV from PCa patients. Tissue and cell line analysis strongly suggested that the status of CDH3 in uEVs is a distal reflection of changes in the expression of this cadherin in the prostate tumor. CDH3 was negatively regulated at the genomic, transcriptional, and epigenetic level in PCa. Our results reveal that uEVs could represent a non-invasive tool to inform about the molecular alterations in PCa.
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Biomarcadores Tumorais/genética , Biomarcadores Tumorais/urina , Caderinas/genética , Caderinas/urina , Vesículas Extracelulares/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/urina , Exossomos/metabolismo , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/patologia , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , Neoplasias da Próstata/patologiaRESUMO
Cellular transformation and cancer progression is accompanied by changes in the metabolic landscape. Master co-regulators of metabolism orchestrate the modulation of multiple metabolic pathways through transcriptional programs, and hence constitute a probabilistically parsimonious mechanism for general metabolic rewiring. Here we show that the transcriptional co-activator peroxisome proliferator-activated receptor gamma co-activator 1α (PGC1α) suppresses prostate cancer progression and metastasis. A metabolic co-regulator data mining analysis unveiled that PGC1α is downregulated in prostate cancer and associated with disease progression. Using genetically engineered mouse models and xenografts, we demonstrated that PGC1α opposes prostate cancer progression and metastasis. Mechanistically, the use of integrative metabolomics and transcriptomics revealed that PGC1α activates an oestrogen-related receptor alpha (ERRα)-dependent transcriptional program to elicit a catabolic state and metastasis suppression. Importantly, a signature based on the PGC1α-ERRα pathway exhibited prognostic potential in prostate cancer, thus uncovering the relevance of monitoring and manipulating this pathway for prostate cancer stratification and treatment.
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Mitocôndrias/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Neoplasias da Próstata/metabolismo , Animais , Modelos Animais de Doenças , Metabolismo Energético/fisiologia , Proteínas de Choque Térmico/metabolismo , Humanos , Masculino , Camundongos , Metástase Neoplásica/patologia , Neoplasias da Próstata/patologia , Receptores de Estrogênio/metabolismo , Receptor ERRalfa Relacionado ao EstrogênioRESUMO
Patient stratification has been instrumental for the success of targeted therapies in breast cancer. However, the molecular basis of metastatic breast cancer and its therapeutic vulnerabilities remain poorly understood. Here we show that PML is a novel target in aggressive breast cancer. The acquisition of aggressiveness and metastatic features in breast tumours is accompanied by the elevated PML expression and enhanced sensitivity to its inhibition. Interestingly, we find that STAT3 is responsible, at least in part, for the transcriptional upregulation of PML in breast cancer. Moreover, PML targeting hampers breast cancer initiation and metastatic seeding. Mechanistically, this biological activity relies on the regulation of the stem cell gene SOX9 through interaction of PML with its promoter region. Altogether, we identify a novel pathway sustaining breast cancer aggressiveness that can be therapeutically exploited in combination with PML-based stratification.
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Neoplasias da Mama/secundário , Neoplasias da Mama/terapia , Proteína da Leucemia Promielocítica/antagonistas & inibidores , Proteína da Leucemia Promielocítica/metabolismo , Animais , Trióxido de Arsênio , Arsenicais/farmacologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Feminino , Técnicas de Silenciamento de Genes , Humanos , Células MCF-7 , Camundongos , Invasividade Neoplásica/genética , Óxidos/farmacologia , Regiões Promotoras Genéticas , Proteína da Leucemia Promielocítica/genética , Fatores de Transcrição SOX9/genética , Fator de Transcrição STAT3/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoAssuntos
Predisposição Genética para Doença , Subunidade alfa de Receptor de Interleucina-2/genética , Esclerose Múltipla/genética , Polimorfismo Genético/genética , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Análise Mutacional de DNA , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Esclerose Múltipla/epidemiologia , Razão de Chances , Rodaminas/metabolismo , Espanha/epidemiologia , População Branca/genéticaRESUMO
Alveolar and embryonal rhabdomyosarcomas are childhood tumors that do not respond well to current chemotherapies. Here, we report that the glycolytic inhibitor 2-deoxyglucose (2-DG) can efficiently promote cell death in alveolar, but not embryonal, rhabdomyosarcoma cell lines. Notably, 2-DG also induced cell differentiation accompanied by downregulation of PAX3/FOXO1a, the chromosome translocation-encoded fusion protein that is a central oncogenic driver in this disease. Cell death triggered by 2-DG was associated with its ability to activate Bax and Bak. Overexpression of the antiapoptotic Bcl-2 homologues Bcl-x(L) and Mcl-1 prevented apoptosis, indicating that cell death proceeds through the mitochondrial pathway. Mechanistic investigations indicated that Mcl-1 downregulation and Noxa upregulation were critical for 2-DG-induced apoptosis. In addition, 2-DG promoted eIF2α phosphorylation and inactivation of the mTOR pathway. Mcl-1 loss and cell death were prevented by downregulation of the endoplasmic reticulum (ER) stress-induced protein ATF4 and by incubating cells in the presence of mannose, which reverted 2-DG-induced ER stress but not ATP depletion. Thus, energetic stresses created by 2-DG were not the primary cause of cell death. Together, our findings suggest that glycolysis inhibitors such as 2-DG may be highly effective in treating alveolar rhabdomyosarcoma and that Noxa could offer a prognostic marker to monitor the efficacy of such agents.