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1.
Front Oncol ; 11: 721624, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34458153

RESUMEN

Autophagy is a highly conserved cellular process in which intracellular proteins and organelles are sequestered and degraded after the fusion of double-membrane vesicles known as autophagosomes with lysosomes. The process of autophagy is dependent on autophagy-related (ATG) proteins. The role of autophagy in cancer is very complex and still elusive. We investigated the expression of ATG proteins in benign nevi, primary and metastatic melanoma tissues using customized tissue microarrays (TMA). Results from immunohistochemistry show that the expression of ATG5 and ATG7 is significantly reduced in melanoma tissues compared to benign nevi. This reduction correlated with changes in the expression of autophagic activity markers, suggesting decreased basal levels of autophagy in primary and metastatic melanomas. Furthermore, the analysis of survival data of melanoma patients revealed an association between reduced ATG5 and ATG7 levels with an unfavourable clinical outcome. Currently, the mechanisms regulating ATG expression levels in human melanoma remains unknown. Using bioinformatic predictions of transcription factor (TF) binding motifs in accessible chromatin of primary melanocytes, we identified new TFs involved in the regulation of core ATGs. We then show that nuclear respiratory factor 1 (NRF1) stimulates the production of mRNA and protein as well as the promoter activity of ATG5 and ATG7. Moreover, NRF1 deficiency increased in vitro migration of melanoma cells. Our results support the concept that reduced autophagic activity contributes to melanoma development and progression, and identifies NRF1 as a novel TF involved in the regulation of both ATG5 and ATG7 genes.

2.
J Invest Dermatol ; 141(12): 2838-2848.e4, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34090855

RESUMEN

Atopic dermatitis and psoriasis are frequent chronic inflammatory skin diseases. Autophagy plays a substantial role in the homeostasis of an organism. Loss or impairment of autophagy is associated with multiple diseases. To investigate the possibility that autophagy plays a role in atopic dermatitis and psoriasis, we investigated the levels of key ATG proteins in human skin specimens as well as in primary human epidermal keratinocytes exposed to inflammatory stimuli in vitro. Although TNF-α facilitated the induction of autophagy in an initial phase, it reduced the levels and enzymatic activities of lysosomal cathepsins in later time periods, resulting in autophagy inhibition. Therefore, TNF-α appears to play a dual role in the regulation of autophagy. The relevance of these in vitro findings was supported by the observation that the protein levels of cathepsins D and L are decreased in both psoriasis and atopic dermatitis skin specimens. Taken together, this study suggests that TNF-α blocks autophagy in keratinocytes after long-term exposure, a mechanism that may contribute to the chronicity of inflammatory diseases of the skin and, perhaps, of other organs.


Asunto(s)
Autofagia/fisiología , Dermatitis Atópica/etiología , Queratinocitos/fisiología , Lisosomas/fisiología , Psoriasis/etiología , Autofagia/efectos de los fármacos , Proteína 5 Relacionada con la Autofagia/análisis , Células Cultivadas , Humanos , Queratinocitos/efectos de los fármacos , Lisosomas/efectos de los fármacos , Proteínas Asociadas a Microtúbulos/análisis , Factor de Necrosis Tumoral alfa/farmacología
3.
J Exp Med ; 217(12)2020 12 07.
Artículo en Inglés | MEDLINE | ID: mdl-32970801

RESUMEN

The depletion of eosinophils represents an efficient strategy to alleviate allergic asthma, but the consequences of prolonged eosinophil deficiency for human health remain poorly understood. We show here that the ablation of eosinophils severely compromises antitumor immunity in syngeneic and genetic models of colorectal cancer (CRC), which can be attributed to defective Th1 and CD8+ T cell responses. The specific loss of GM-CSF signaling or IRF5 expression in the eosinophil compartment phenocopies the loss of the entire lineage. GM-CSF activates IRF5 in vitro and in vivo and can be administered recombinantly to improve tumor immunity. IL-10 counterregulates IRF5 activation by GM-CSF. CRC patients whose tumors are infiltrated by large numbers of eosinophils also exhibit robust CD8 T cell infiltrates and have a better prognosis than patients with eosinophillow tumors. The combined results demonstrate a critical role of eosinophils in tumor control in CRC and introduce the GM-CSF-IRF5 axis as a critical driver of the antitumor activities of this versatile cell type.


Asunto(s)
Eosinófilos/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Inmunidad , Factores Reguladores del Interferón/metabolismo , Neoplasias/inmunología , Transducción de Señal , Células TH1/inmunología , Adenoma/tratamiento farmacológico , Adenoma/inmunología , Adenoma/patología , Animales , Carcinogénesis/efectos de los fármacos , Carcinogénesis/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/inmunología , Neoplasias del Colon/patología , Eosinófilos/efectos de los fármacos , Eosinófilos/patología , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunidad/efectos de los fármacos , Interleucina-10/metabolismo , Interleucina-5/metabolismo , Intestinos/patología , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/patología , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Masculino , Ratones Endogámicos C57BL , Neoplasias/metabolismo , Neoplasias/patología , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Análisis de Supervivencia , Células TH1/efectos de los fármacos , Transcripción Genética/efectos de los fármacos , Transgenes , Microambiente Tumoral/efectos de los fármacos
4.
Arch Toxicol ; 94(10): 3527-3539, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32651653

RESUMEN

Amiodarone is a widely used antiarrhythmic drug that can cause the development of steatohepatitis as well as liver fibrosis and cirrhosis. The molecular mechanisms of amiodarone-mediated liver injury remain largely unknown. We therefore analyzed amiodarone-mediated hepatocellular injury in patients with chronic heart failure, in primary hepatocytes and HepG2 cells. We found that amiodarone-treated patients with chronic heart failure revealed significantly higher serum levels of caspase-cleaved keratin-18, an apoptosis biomarker, compared to healthy individuals or patients not receiving amiodarone. Furthermore, amiodarone treatment of hepatocytes resulted in apoptosis associated with lipid accumulation and ER-stress induction. Liver cell steatosis was accompanied by enhanced de novo lipogenesis which, after reaching peak levels, declined together with decreased activation of ER stress. The decline of amiodarone-mediated lipotoxicity was associated with protective autophagy induction. In contrast, in hepatocytes treated with the autophagy inhibitor chloroquine as well as in autophagy gene (ATG5 or ATG7)-deficient hepatocytes, amiodarone-triggered toxicity was increased. In conclusion, we demonstrate that amiodarone induces lipid accumulation associated with ER stress and apoptosis in hepatocytes, which is mirrored by increased keratin-18 fragment serum levels in amiodarone-treated patients. Autophagy reduces amiodarone-mediated lipotoxicity and could provide a therapeutic strategy for protection from drug-induced liver injury.


Asunto(s)
Amiodarona/efectos adversos , Autofagia , Enfermedad Hepática Inducida por Sustancias y Drogas , Hepatocitos/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Anciano , Antiarrítmicos/efectos adversos , Apoptosis/efectos de los fármacos , Sistemas CRISPR-Cas , Supervivencia Celular , Células Cultivadas , Cloroquina/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Femenino , Técnicas de Inactivación de Genes , Células Hep G2 , Humanos , Queratina-18/sangre , Masculino
5.
Oncogene ; 39(26): 4944-4955, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32493957

RESUMEN

Endophilin B1, also known as BAX-interacting protein 1 (BIF-1), is part of the endophilin B protein family, and is a multifunctional protein involved in the regulation of apoptosis, autophagy, and mitochondrial morphology. The role of BIF-1 in cancer is controversial since previous reports indicated to both tumor-promoting and tumor-suppressive roles, perhaps depending on the cancer cell type. In the present study, we report that BIF-1 is significantly downregulated in both primary and metastatic melanomas, and that patients with high levels of BIF-1 expression exhibited a better overall survival. Depleting BIF-1 using CRISPR/Cas9 technology in melanoma cells resulted in higher proliferation rates both in vitro and in vivo, a finding that was associated with increased ATP production, metabolic acidification, and mitochondrial respiration. We also observed mitochondrial hyperpolarization, but no increase in the mitochondrial content of BIF-1-knockout melanoma cells. In contrast, such knockout melanoma cells were equally sensitive to anticancer drug- or UV irradiation-induced cell death, and exhibited similar autophagic activities as compared with control cells. Taken together, it appears that downregulation of BIF-1 contributes to tumorigenesis in cutaneous melanoma by upregulating mitochondrial respiration and metabolism, independent of its effect on apoptosis and autophagy.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Adenosina Trifosfato/metabolismo , Regulación Neoplásica de la Expresión Génica , Melanoma/genética , Mitocondrias/metabolismo , Neoplasias Cutáneas/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Apoptosis/genética , Autofagia/genética , Línea Celular Tumoral , Regulación hacia Abajo , Glucólisis , Humanos , Estimación de Kaplan-Meier , Melanoma/metabolismo , Melanoma/terapia , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/terapia , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
6.
Cell Death Differ ; 27(6): 1965-1980, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-31844253

RESUMEN

In contrast to the "Warburg effect" or aerobic glycolysis earlier generalized as a phenomenon in cancer cells, more and more recent evidence indicates that functional mitochondria are pivotal for ensuring the energy supply of cancer cells. Here, we report that cancer cells with reduced autophagy-related protein 12 (ATG12) expression undergo an oncotic cell death, a phenotype distinct from that seen in ATG5-deficient cells described before. In addition, using untargeted metabolomics with ATG12-deficient cancer cells, we observed a global reduction in cellular bioenergetic pathways, such as ß-oxidation (FAO), glycolysis, and tricarboxylic acid cycle activity, as well as a decrease in mitochondrial respiration as monitored with Seahorse experiments. Analyzing the biogenesis of mitochondria by quantifying mitochondrial DNA content together with several mitochondrion-localizing proteins indicated a reduction in mitochondrial biogenesis in ATG12-deficient cancer cells, which also showed reduced hexokinase II expression and the upregulation of uncoupling protein 2. ATG12, which we observed in normal cells to be partially localized in mitochondria, is upregulated in multiple types of solid tumors in comparison with normal tissues. Strikingly, mouse xenografts of ATG12-deficient cells grew significantly slower as compared with vector control cells. Collectively, our work has revealed a previously unreported role for ATG12 in regulating mitochondrial biogenesis and cellular energy metabolism and points up an essential role for mitochondria as a failsafe mechanism in the growth and survival of glycolysis-dependent cancer cells. Inducing oncosis by imposing an ATG12 deficiency in solid tumors might represent an anticancer therapy preferable to conventional caspase-dependent apoptosis that often leads to undesirable consequences, such as incomplete cancer cell killing and a silencing of the host immune system.


Asunto(s)
Proteína 12 Relacionada con la Autofagia/fisiología , Mitocondrias/metabolismo , Neoplasias/metabolismo , Animales , Línea Celular Tumoral , Metabolismo Energético , Glucólisis , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID
8.
Cell Death Differ ; 26(4): 715-727, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30737475

RESUMEN

Autophagy is well equipped functionally to isolate microbial pathogens in autophagosomes and to carry out their clearance by dismemberment in the course of catabolic processes in the lysosome. Clearly, this is a non-metabolic function of autophagy that impacts strongly on the immune system. While in a preceding article on neutrophils, eosinophils, mast cells, and natural killer cells our focus was on the role of autophagy in regulating innate immune cell differentiation, degranulation, phagocytosis and extracellular trap formation, here we discuss monocytes/macrophages and dendritic cells, specifically, the influence of autophagy on functional cellular responses, such as phagocytosis, antigen presentation, cytokine production, control of inflammasome activation, tolerance and the consequences for overall host defense.


Asunto(s)
Presentación de Antígeno/inmunología , Autofagia , Células Dendríticas/inmunología , Inmunidad Innata , Macrófagos/inmunología , Monocitos/inmunología , Animales , Presentación de Antígeno/genética , Autofagia/genética , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Citocinas/metabolismo , Células Dendríticas/metabolismo , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Inflamasomas/inmunología , Inflamasomas/metabolismo , Macrófagos/metabolismo , Macrófagos/microbiología , Monocitos/metabolismo , Fagocitosis/genética , Fagocitosis/inmunología , Transducción de Señal/inmunología
9.
Cell Death Differ ; 26(4): 703-714, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30737478

RESUMEN

Autophagy is an evolutionally conserved, highly regulated catabolic process that combines cellular functions required for the regulation of metabolic balance under conditions of stress with those needed for the degradation of damaged cell organelles via the lysosomal machinery. The importance of autophagy for cell homeostasis and survival has long been appreciated. Recent data suggest that autophagy is also involved in non-metabolic functions that impact the immune system. Here, we reflect in two review articles the recent literature pointing to an important role for autophagy in innate immune cells. In this article, we focus on neutrophils, eosinophils, mast cells, and natural killer cells. We mainly discuss the influence of autophagy on functional cellular responses and its importance for overall host defense. In the companion review, we present the role of autophagy in the functions performed by monocytes/macrophages and dendritic cells.


Asunto(s)
Autofagia/inmunología , Eosinófilos/inmunología , Inmunidad Innata , Células Asesinas Naturales/inmunología , Mastocitos/inmunología , Neutrófilos/metabolismo , Animales , Autofagia/genética , Autofagia/fisiología , Muerte Celular/genética , Muerte Celular/inmunología , Eosinófilos/metabolismo , Trampas Extracelulares/inmunología , Trampas Extracelulares/metabolismo , Trampas Extracelulares/microbiología , Humanos , Inmunidad Innata/efectos de los fármacos , Inmunidad Innata/genética , Células Asesinas Naturales/metabolismo , Células Asesinas Naturales/microbiología , Células Asesinas Naturales/virología , Mastocitos/metabolismo , Mastocitos/microbiología , Neutrófilos/inmunología , Neutrófilos/microbiología
10.
PLoS One ; 13(11): e0207019, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30408085

RESUMEN

INTRODUCTION: Finding new markers to assess prognosis of melanoma without the necessity to perform a surgical interventions is an important goal in melanoma research. The current study aimed to assess the correlation of clinical course and prognosis of primary and metastatic melanoma with expression of VEGF family and their receptors. METHODS: A ngTMA block was made from the randomly selected paraffin tissue blocks of the patients with melanocytic nevi, primary and metastatic melanoma. Then sections cut from ngTMA-block were immunohistochemically stained with proper antibodies. Expression of these proteins was investigated using automated image analysis and compared among the study groups. RESULTS: We analyzed the tissue of 238 patients with following diagnoses: 101 (42.4%) with a diagnosis of nevus, 86 (36.1%) Malignant melanoma and 51 (21.4%) metastasis. Median follow-up time for the malignant lesions was 5.71 years. Among the tested antigen, VEGF-C (p = 0.016), VEGF-R2 (p<0.001) and VEGF-R3 (p = 0.002) were significantly higher expressed in the metastatic tissues. When these scores were assessed in multiple regression models, the only independent factor linked to patient's diagnosis was VEGF-R2 (p<0.001). In addition, groups of highly correlated variables (VEGF-C and VEGF-R3, VEGF-A and VEGF-R1) were found to form separate sub-clusters. On the other side, high values of VEGF-C were associated with both overall and disease-free survival with a statically significant HR of 2.76 (95% CI: 1.27, 5.98; p = 0.01) and 2.82 (95%CI: 1.62, 4.91; p<0.001), respectively. CONCLUSIONS: This study shows that VEGF-C and VEGF-R2 might represent new prognostic marker in MM. However, further prospective studies are warranted to test their real efficacy as a prognostic marker.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Melanoma/diagnóstico , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Análisis de Matrices Tisulares/métodos , Factores de Crecimiento Endotelial Vascular/metabolismo , Adulto , Anciano , Automatización , Supervivencia sin Enfermedad , Femenino , Humanos , Interpretación de Imagen Asistida por Computador , Estimación de Kaplan-Meier , Modelos Logísticos , Masculino , Melanoma/mortalidad , Melanoma/patología , Persona de Mediana Edad , Metástasis de la Neoplasia , Nevo Pigmentado/diagnóstico , Nevo Pigmentado/patología , Análisis de Componente Principal , Isoformas de Proteínas/metabolismo
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