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1.
Sensors (Basel) ; 22(12)2022 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-35746350

RESUMEN

The development of predictive in vitro sensing tools able to provide rapid information on the different bioactivities of a sample is of pivotal importance, not only to monitor environmental toxicants, but also to understand their mechanisms of action on diverse molecular pathways. This mechanistic understanding is highly important for the characterization of toxicological hazards, and for the risk assessment of chemicals and environmental samples such as surface waters and effluents. Prompted by this need, we developed and optimized a straightforward bioluminescent multiplexed assay which enables the measurement of four bioactivities, selected for their relevance from a toxicological perspective, in bioluminescent microtissues. The assay was developed to monitor inflammatory, antioxidant, and toxic activity, and the presence of heavy metals, and was successfully applied to the analysis of river water samples, showing potential applicability for environmental analyses. The assay, which does not require advanced equipment, can be easily implemented in general laboratories equipped with basic cell culture facilities and a luminometer.


Asunto(s)
Metales Pesados , Bioensayo , Agua Dulce , Mediciones Luminiscentes
2.
Cells ; 11(4)2022 02 13.
Artículo en Inglés | MEDLINE | ID: mdl-35203299

RESUMEN

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the pathogenic agent of Coronavirus-Induced Disease-2019 (COVID-19), a multi-organ syndrome which primarily targets the respiratory system. In this review, considering the large amount of data pointing out the role of the Aryl hydrocarbon Receptor (AhR) in the inflammatory response and in the modulation of innate and adaptive immunity, we describe some mechanisms that strongly suggest its involvement in the management of COVID-19's inflammatory framework. It regulates both the expression of Angiotensin Converting Enzyme-2 (ACE-2) and its stabilizing partner, the Broad neutral Amino acid Transporter 1 (B0AT1). It induces Indolamine 2,3 dioxygenase (IDO-1), the enzyme which, starting from Tryptophan (Trp), produces Kynurenine (Kyn, Beta-Anthraniloyl-L-Alanine). The accumulation of Kyn and the depletion of Trp arrest T cell growth and induce apoptosis, setting up an immune-tolerant condition, whereas AhR and interferon type I (IFN-I) build a mutual inhibitory loop that also involves NF-kB and limits the innate response. AhR/Kyn binding boosts the production of Interleukin-6 (IL-6), thus reinforcing the inflammatory state and counteracting the IDO-dependent immune tolerance in the later stage of COVID-19. Taken together, these data depict a framework where sufficient clues suggest the possible participation of AhR in the management of COVID-19 inflammation, thus indicating an additional therapeutic target for this disease.


Asunto(s)
COVID-19/metabolismo , Receptores de Hidrocarburo de Aril/metabolismo , SARS-CoV-2/metabolismo , Inmunidad Adaptativa/inmunología , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Enzima Convertidora de Angiotensina 2/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/fisiología , COVID-19/inmunología , COVID-19/transmisión , Humanos , Inmunidad Innata/inmunología , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Inflamación/inmunología , Quinurenina/metabolismo , Receptores de Hidrocarburo de Aril/fisiología , SARS-CoV-2/patogenicidad , Transducción de Señal , Triptófano/metabolismo
3.
J Hum Evol ; 161: 103093, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34749003

RESUMEN

Neanderthal foot bone proportions and morphology are mostly indistinguishable from those of Homo sapiens, with the exception of several distinct Neanderthal features in the talus. The biomechanical implications of these distinct talar features remain contentious, fueling debate around the adaptive meaning of this distinctiveness. With the aim of clarifying this controversy, we test phylogenetic and behavioral factors as possible contributors, comparing tali of 10 Neanderthals and 81 H. sapiens (Upper Paleolithic and Holocene hunter-gatherers, agriculturalists, and postindustrial group) along with the Clark Howell talus (Omo, Ethiopia). Variation in external talar structures was assessed through geometric morphometric methods, while bone volume fraction and degree of anisotropy were quantified in a subsample (n = 45). Finally, covariation between point clouds of site-specific trabecular variables and surface landmark coordinates was assessed. Our results show that although Neanderthal talar external and internal morphologies were distinct from those of H. sapiens groups, shape did not significantly covary with either bone volume fraction or degree of anisotropy, suggesting limited covariation between external and internal talar structures. Neanderthal external talar morphology reflects ancestral retentions, along with various adaptations to high levels of mobility correlated to their presumably unshod hunter-gatherer lifestyle. This pairs with their high site-specific trabecular bone volume fraction and anisotropy, suggesting intense and consistently oriented locomotor loading, respectively. Relative to H.sapiens, Neanderthals exhibit differences in the talocrural joint that are potentially attributable to cultural and locomotor behavior dissimilarity, a talonavicular joint that mixes ancestral and functional traits, and a derived subtalar joint that suggests a predisposition for a pronated foot during stance phase. Overall, Neanderthal talar variation is attributable to mobility strategy and phylogenesis, while H. sapiens talar variation results from the same factors plus footwear. Our results suggest that greater Neanderthal body mass and/or higher mechanical stress uniquely led to their habitually pronated foot posture.


Asunto(s)
Hombre de Neandertal , Astrágalo , Animales , Fósiles , Humanos , Filogenia , Postura , Estrés Mecánico , Astrágalo/anatomía & histología
4.
Int J Mol Sci ; 21(15)2020 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-32722276

RESUMEN

Aryl hydrocarbon receptor (AhR), an evolutionary conserved transcription factor, is a pleiotropic signal transductor. Thanks to its promiscuous ligand binding domain, during the evolution of eukaryotic cells its developmental functions were integrated with biosensor functions. Its activation by a multitude of endogenous and exogenous molecules stimulates its participation in several pathways, some of which are linked to inflammation and breast cancer (BC). Over time, the study of this malignancy has led to the identification of several therapeutic targets in cancer cells. An intense area of study is dedicated to BC phenotypes lacking adequate targets. In this context, due to its high constitutive activation in BC, AhR is currently gaining more and more attention. In this review, I have considered its interactions with: 1. the immune system, whose dysregulation is a renowned cancer hallmark; 2. interleukin 6 (IL6) which is a pivotal inflammatory marker and is closely correlated to breast cancer risk; 3. NF-kB, another evolutionary conserved transcription factor, which plays a key role in immunoregulatory functions, inflammatory response and breast carcinogenesis; 4. kynurenine, a tryptophan-derived ligand that activates and bridges AhR to chronic inflammation and breast carcinogenesis. Overall, the data here presented form an interesting framework where AhR is an interesting connector between inflammation and BC.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Neoplasias de la Mama/metabolismo , Carcinogénesis/metabolismo , Proteínas de Neoplasias/metabolismo , Receptores de Hidrocarburo de Aril/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Carcinogénesis/genética , Femenino , Humanos , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Proteínas de Neoplasias/genética , Receptores de Hidrocarburo de Aril/genética
5.
Am J Physiol Cell Physiol ; 318(6): C1078-C1082, 2020 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-32208988

RESUMEN

Aryl hydrocarbon receptor (AhR), a highly conserved intracellular transcription factor, is activated by a plethora of ligands of both exogenous and endogenous nature. Besides activating xenobiotic-metabolizing enzymes, it is involved in the differentiation and development of hematopoietic, hepatic, nervous and immune systems. More and more data describe its role in the regulation of immune responses and in the onset and progression of inflammation. Particularly, established results view AhR as a downstream target of inflammatory molecules, since its transcription is regulated by the inflammatory cascade. Interleukin 6 (IL-6) has been described to sustain early stages of inflammation and to influence the expression of AhR either directly, following signal transducer and activator of transcription 3 (STAT3) activation, or in combination with other inflammatory mediators, e.g., transforming growth factor-ß (TGF-ß). In selected inflammatory milieus, once activated, AhR interacts with its targets including the IL-6 promoter, thus originating an autoinflammatory loop. This perspective review brings together evidence that, in some IL-6-driven pathways, AhR is a downstream target that amplifies the duration and extent of inflammation. Considering that many inflammatory mediators can also trigger the activities of AhR as biosensor and activator of xenobiotics metabolism, this issue is of pivotal importance. The individual susceptibly to some environmental ligands of AhR can be probably explained by considering the individual inflammatory state, which could additionally fuel the proinflammatory activity of AhR. Thus, AhR could be considered a transductor of a dynamic, bidirectional connection between internal and external environmental stimuli and the inflammatory response.


Asunto(s)
Mediadores de Inflamación/metabolismo , Inflamación/metabolismo , Receptores de Hidrocarburo de Aril/metabolismo , Animales , Humanos , Inflamación/inmunología , Inflamación/fisiopatología , Mediadores de Inflamación/inmunología , Interleucina-6/metabolismo , Quinurenina/metabolismo , Receptores de Hidrocarburo de Aril/inmunología , Factor de Transcripción STAT3/metabolismo , Transducción de Señal
6.
Curr Cancer Drug Targets ; 16(2): 186-97, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26310524

RESUMEN

Epidemiological data suggest that Non Steroidal Anti Inflammatory Drugs (NSAIDs) and Cyclooxygenase 2 (COX2) inhibitors (COXibs) can exert chemopreventive and antitumour effects in many human neoplasia. This is particularly true in colon cancer (CC), where the regular assumption of these molecules has been shown to exert chemopreventive and chemotherapeutic effects. Since the late '90s, there has been a progressive increase in experimental evidence, indicating that in CC the antiproliferative effects of NSAIDs and COXibs could be both dependent on and independent of COXs inhibition, and that these effects do not necessarily exclude each other. This review will examine some of these COX-independent cellular pathways, with a focus on those involved in the inhibition of CC cells proliferation through transcription factors crosstalk.


Asunto(s)
Anticarcinógenos/uso terapéutico , Transformación Celular Neoplásica/efectos de los fármacos , Inhibidores de la Ciclooxigenasa/uso terapéutico , Inflamación/prevención & control , Neoplasias/prevención & control , Animales , Ciclo Celular/efectos de los fármacos , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Regulación Neoplásica de la Expresión Génica , Humanos , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Mediadores de Inflamación/metabolismo , Neoplasias/enzimología , Neoplasias/genética , Neoplasias/patología , Factores de Riesgo , Transducción de Señal/efectos de los fármacos , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
7.
Carcinogenesis ; 36 Suppl 1: S232-53, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26106141

RESUMEN

An emerging area in environmental toxicology is the role that chemicals and chemical mixtures have on the cells of the human immune system. This is an important area of research that has been most widely pursued in relation to autoimmune diseases and allergy/asthma as opposed to cancer causation. This is despite the well-recognized role that innate and adaptive immunity play as essential factors in tumorigenesis. Here, we review the role that the innate immune cells of inflammatory responses play in tumorigenesis. Focus is placed on the molecules and pathways that have been mechanistically linked with tumor-associated inflammation. Within the context of chemically induced disturbances in immune function as co-factors in carcinogenesis, the evidence linking environmental toxicant exposures with perturbation in the balance between pro- and anti-inflammatory responses is reviewed. Reported effects of bisphenol A, atrazine, phthalates and other common toxicants on molecular and cellular targets involved in tumor-associated inflammation (e.g. cyclooxygenase/prostaglandin E2, nuclear factor kappa B, nitric oxide synthesis, cytokines and chemokines) are presented as example chemically mediated target molecule perturbations relevant to cancer. Commentary on areas of additional research including the need for innovation and integration of systems biology approaches to the study of environmental exposures and cancer causation are presented.


Asunto(s)
Carcinógenos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/efectos adversos , Inflamación/inducido químicamente , Inflamación/inmunología , Neoplasias/inducido químicamente , Neoplasias/inmunología , Animales , Carcinogénesis/inducido químicamente , Carcinogénesis/inmunología , Humanos , Inmunidad Innata/efectos de los fármacos , Inmunidad Innata/inmunología , Neoplasias/etiología , Riesgo
8.
Pancreas ; 43(1): 53-63, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24201777

RESUMEN

OBJECTIVES: Resistance to gemcitabine is one of the main causes of treatment failure in pancreatic cancer. Compelling evidences have shown the involvement of nuclear factor κB (NF-κB) activation in such phenomenon. The protease inhibitor gabexate mesilate has been shown to inhibit NF-κB. We here investigated if combined treatment with this drug could improve gemcitabine antitumoral efficacy in pancreatic cancer cells. METHODS: The effect of gabexate mesilate and gemcitabine, both used at concentrations achievable in human plasma, was assessed on in vitro pancreatic cancer cell growth, invasion, and tumor angiogenesis. The molecular mechanism at the basis of these effects was also investigated. RESULTS: Gabexate mesilate significantly increased gemcitabine anti-invasive and antiangiogenic efficacy. This effect was related to inhibition of gemcitabine-induced NF-κB activation by gabexate mesilate, which prevented RelA/p65 nuclear translocation and resulted in metalloproteinase 2, metalloproteinase 9, vascular endothelial growth factor, and interleukin 8 down-regulation. Combined treatment with gabexate mesilate also inhibited gemcitabine-induced extracellular-regulated kinase 1/2 and AKT activation by increased expression of Raf kinase inhibitor protein and phosphatase and tensin homolog. CONCLUSIONS: Combined treatment with gabexate mesilate sensitizes pancreatic cancer cells to gemcitabine by inhibition of the NF-κB pathway. The efficacy of this therapeutic strategy in pancreatic cancer patients remains to be established and deserves future clinical investigation.


Asunto(s)
Proliferación Celular/efectos de los fármacos , Desoxicitidina/análogos & derivados , Gabexato/farmacología , FN-kappa B/antagonistas & inhibidores , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/farmacología , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Western Blotting , Línea Celular , Línea Celular Tumoral , Desoxicitidina/administración & dosificación , Desoxicitidina/farmacología , Regulación hacia Abajo/efectos de los fármacos , Evaluación Preclínica de Medicamentos/métodos , Activación Enzimática/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Gabexato/administración & dosificación , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Interleucina-8/genética , Interleucina-8/metabolismo , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , FN-kappa B/genética , FN-kappa B/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Inhibidores de Serina Proteinasa/administración & dosificación , Inhibidores de Serina Proteinasa/farmacología , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Gemcitabina
9.
PLoS One ; 8(1): e54968, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23372804

RESUMEN

AIMS: Cancer stem cell biology is tightly connected to the regulation of the pro-inflammatory cytokine network. The concept of cancer stem cells "inflammatory addiction" leads to envisage the potential role of anti-inflammatory molecules as new anti-cancer targets. Here we report on the relationship between nuclear receptors activity and the modulation of the pro-inflammatory phenotype in breast cancer stem cells. METHODS: Breast cancer stem cells were expanded as mammospheres from normal and tumor human breast tissues and from tumorigenic (MCF7) and non tumorigenic (MCF10) human breast cell lines. Mammospheres were exposed to the supernatant of breast tumor and normal mammary gland tissue fibroblasts. RESULTS: In mammospheres exposed to the breast tumor fibroblasts supernatant, autocrine tumor necrosis factor-α signalling engenders the functional interplay between peroxisome proliferator activated receptor-α and hypoxia inducible factor-1α (PPARα/HIF1α). The two proteins promote mammospheres formation and enhance each other expression via miRNA130b/miRNA17-5p-dependent mechanism which is antagonized by PPARγ. Further, the PPARα/HIF1α interplay regulates the expression of the pro-inflammatory cytokine interleukin-6, the hypoxia survival factor carbonic anhydrase IX and the plasma lipid carrier apolipoprotein E. CONCLUSION: Our data demonstrate the importance of exploring the role of nuclear receptors (PPARα/PPARγ) in the regulation of pro-inflammatory pathways, with the aim to thwart breast cancer stem cells functioning.


Asunto(s)
Apolipoproteínas E/metabolismo , Neoplasias de la Mama/metabolismo , Anhidrasas Carbónicas/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Células Madre Neoplásicas/metabolismo , PPAR alfa/metabolismo , Apolipoproteínas E/genética , Comunicación Autocrina , Neoplasias de la Mama/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Medios de Cultivo Condicionados/farmacología , Femenino , Fibroblastos/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Modelos Biológicos , PPAR alfa/genética , PPAR gamma/genética , PPAR gamma/metabolismo , Unión Proteica , Esferoides Celulares , Células Tumorales Cultivadas , Factor de Necrosis Tumoral alfa/metabolismo
10.
Cancer Lett ; 321(2): 187-94, 2012 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-22343320

RESUMEN

The ability to induce changes in cell membrane properties is nowadays considered an additional mechanism to explain the pharmacological effects of non-steroidal anti-inflammatory drugs (NSAIDs). We previously demonstrated that the NSAID Licofelone, a dual cyclooxygenase/5-lipoxygenase inhibitor, triggers apoptosis in HCA-7 colon cancer cells independently from the inhibition of these enzymes. Here, we provide evidence that, in HCA-7 cells, the pro-apoptotic effect of this drug relies, at least in part, on its ability to inhibit epidermal growth factor receptor (EGFR) signalling by a decrease of cell membrane fluidity. Indeed, Licofelone induced a relevant change in the relative proportions of some saturated, monounsaturated and polyunsaturated fatty acids constituting HCA-7 phospholipid fraction and significantly increased the levels of cholesterol in HCA-7 cell membrane. All of these changes resulted in a remarkable decrease of membrane fluidity. Such phenomenon was associated with the block of EGFR kinase activity and of its downstream targets, the p44-42 mitogen-activated protein kinase (MAPK) and AKT cascades, whose inhibitions were found to induce apoptosis in HCA-7 cells. Overall, these findings provide a new additional mechanism by which NSAIDs are effective toward colon cancer cells.


Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Apoptosis/efectos de los fármacos , Membrana Celular/metabolismo , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon/metabolismo , Receptores ErbB/efectos de los fármacos , Fluidez de la Membrana/efectos de los fármacos , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Pirroles/farmacología , Transducción de Señal/efectos de los fármacos , Antiinflamatorios no Esteroideos/uso terapéutico , Western Blotting , Línea Celular Tumoral , Neoplasias del Colon/tratamiento farmacológico , Receptores ErbB/metabolismo , Técnica del Anticuerpo Fluorescente , Humanos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Pirroles/uso terapéutico
11.
J Cell Physiol ; 225(3): 682-91, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20509143

RESUMEN

Extracellular and intracellular mediators of inflammation, such as tumor necrosis factor alpha (TNFα) and NF-kappaB (NF-κB), play major roles in breast cancer pathogenesis, progression and relapse. SLUG, a mediator of the epithelial-mesenchymal transition process, is over-expressed in CD44(+)/CD24(-) tumor initiating breast cancer cells and in basal-like carcinoma, a subtype of aggressive breast cancer endowed with a stem cell-like gene expression profile. Cancer stem cells also over-express members of the pro-inflammatory NF-κB network, but their functional relationship with SLUG expression in breast cancer cells remains unclear. Here, we show that TNFα treatment of human breast cancer cells up-regulates SLUG with a dependency on canonical NF-κB/HIF1α signaling, which is strongly enhanced by p53 inactivation. Moreover, SLUG up-regulation engenders breast cancer cells with stem cell-like properties including enhanced expression of CD44 and Jagged-1 in conjunction with estrogen receptor alpha down-regulation, growth as mammospheres, and extracellular matrix invasiveness. Our results reveal a molecular mechanism whereby TNFα, a major pro-inflammatory cytokine, imparts breast cancer cells with stem cell-like features, which are connected to increased tumor aggressiveness.


Asunto(s)
Neoplasias de la Mama/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Mediadores de Inflamación/metabolismo , FN-kappa B/metabolismo , Células Madre Neoplásicas/metabolismo , Factores de Transcripción/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Proteínas de Unión al Calcio/metabolismo , Línea Celular Tumoral , Receptor alfa de Estrógeno/metabolismo , Matriz Extracelular/metabolismo , Femenino , Humanos , Receptores de Hialuranos/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteína Jagged-1 , Proteínas de la Membrana/metabolismo , FN-kappa B/genética , Invasividad Neoplásica , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/inmunología , Células Madre Neoplásicas/patología , Fenotipo , Interferencia de ARN , Proteínas Recombinantes/metabolismo , Proteínas Serrate-Jagged , Transducción de Señal , Factores de Transcripción de la Familia Snail , Esferoides Celulares , Factores de Transcripción/genética , Transfección , Proteína p53 Supresora de Tumor/metabolismo , Regulación hacia Arriba
12.
Carcinogenesis ; 29(2): 371-80, 2008 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18033773

RESUMEN

Nowadays, no data are available concerning the potential use of dual cyclooxygenase (COX)/5-lipoxygenase (LOX) inhibitors as anticancer agents in colon cancer treatment. Here, we report, for the first time, that the dual COX/5-LOX inhibitor licofelone triggers apoptosis in a dose- and time-dependent manner in HCA-7 colon cancer cells. Induction of apoptosis was related to the recruitment of the intrinsic mitochondrial apoptotic pathway, as shown by loss in mitochondrial membrane potential, cytochrome c release, caspase-9 and 3 activation and poly-(ADP-ribose)polymerase-1 cleavage. Moreover, licofelone induced the cleavage of the full-length p21(Bax) into p18(Bax), a more potent inducer of the apoptotic process than the uncleaved form. Pre-treatment of HCA-7 cells with the pan-caspase inhibitor z-VAD-fmk significantly blocked licofelone-induced apoptosis, confirming that this process occurred primarily in a caspase-dependent pathway. We also present evidences that licofelone was able to affect the arachidonic acid (AA) cascade, as it blocked the activity of 5-LOX and COX enzymes, and it induced, through the phosphorylation of cytoplasmic phospholipase A(2) (cPLA(2)), the release of unesterified AA from HCA-7 membrane phospholipids. However, apoptosis induction was not related to the ability of licofelone to affect the AA cascade, since neither exogenous prostaglandin E(2) and leukotriene B(4) addition, nor pharmacological inhibition of cPLA(2), was able to rescue HCA-7 cells from apoptosis. Even if further studies are needed to clarify the mechanism of licofelone-induced apoptosis, this study suggests that this drug, as well as similar dual COX/5-LOX inhibitors, may represent a novel and promising approach in colon cancer treatment.


Asunto(s)
Acetatos/farmacología , Apoptosis , Ácido Araquidónico/metabolismo , Neoplasias del Colon/metabolismo , Inhibidores de la Ciclooxigenasa/farmacología , Regulación Neoplásica de la Expresión Génica , Inhibidores de la Lipooxigenasa/farmacología , Mitocondrias/metabolismo , Prostaglandina-Endoperóxido Sintasas/metabolismo , Pirroles/farmacología , Línea Celular Tumoral , Supervivencia Celular , Citosol/metabolismo , Humanos , Potencial de la Membrana Mitocondrial
13.
J Clin Invest ; 117(12): 3988-4002, 2007 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18060036

RESUMEN

High serum levels of IL-6 correlate with poor outcome in breast cancer patients. However, no data are available on the relationship between IL-6 and mammary stem/progenitor cells, which may fuel the genesis of breast cancer in vivo. Herein, we address this issue in the MCF-7 breast cancer cell line and in primary human mammospheres (MS), multicellular structures enriched in stem/progenitor cells of the mammary gland. MS from node invasive breast carcinoma tissues expressed IL-6 mRNA at higher levels than did MS from matched non-neoplastic mammary glands. In addition, IL-6 mRNA was detected only in basal-like breast carcinoma tissues, an aggressive breast carcinoma variant showing stem cell features. IL-6 treatment triggered Notch-3-dependent upregulation of the Notch ligand Jagged-1 and promotion of MS and MCF-7-derived spheroid growth. Moreover, IL-6 induced Notch-3-dependent upregulation of the carbonic anhydrase IX gene and promoted a hypoxia-resistant/invasive phenotype in MCF-7 cells and MS. Finally, autocrine IL-6 signaling relied upon Notch-3 activity to sustain the aggressive features of MCF-7-derived hypoxia-selected cells. In conclusion, these data support the hypothesis that IL-6 induces malignant features in Notch-3-expressing stem/progenitor cells from human ductal breast carcinoma and normal mammary gland.


Asunto(s)
Neoplasias de la Mama/metabolismo , Carcinoma Ductal/metabolismo , Interleucina-6/metabolismo , Glándulas Mamarias Humanas/metabolismo , Proteínas de Neoplasias/metabolismo , Esferoides Celulares/metabolismo , Células Madre/metabolismo , Antígenos de Neoplasias/biosíntesis , Antígenos de Neoplasias/genética , Comunicación Autocrina/efectos de los fármacos , Comunicación Autocrina/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Proteínas de Unión al Calcio , Anhidrasa Carbónica IX , Anhidrasas Carbónicas/biosíntesis , Anhidrasas Carbónicas/genética , Carcinoma Ductal/genética , Carcinoma Ductal/patología , Hipoxia de la Célula/efectos de los fármacos , Hipoxia de la Célula/genética , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Péptidos y Proteínas de Señalización Intercelular , Interleucina-6/genética , Interleucina-6/farmacología , Proteína Jagged-1 , Glándulas Mamarias Humanas/patología , Proteínas de la Membrana , Invasividad Neoplásica , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Neoplásico/biosíntesis , ARN Neoplásico/genética , Receptor Notch3 , Receptores Notch/genética , Receptores Notch/metabolismo , Proteínas Serrate-Jagged , Esferoides Celulares/patología , Células Madre/patología , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genética
14.
Am J Physiol Regul Integr Comp Physiol ; 291(3): R664-73, 2006 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16601263

RESUMEN

In mammals, estrogens have dose- and cell-type-specific effects on immune cells and may act as pro- and anti-inflammatory stimuli, depending on the setting. In the bivalve mollusc Mytilus, the natural estrogen 17beta-estradiol (E(2)) has been shown to affect neuroimmune functions. We have investigated the immunomodulatory role of E(2) in Mytilus hemocytes, the cells responsible for the innate immune response. E(2) at 5-25 nM rapidly stimulated phagocytosis and oxyradical production in vitro; higher concentrations of E(2) inhibited phagocytosis. E(2)-induced oxidative burst was prevented by the nitric oxide (NO) synthase inhibitor N(G)-monomethyl-L-arginine and superoxide dismutase, indicating involvement of NO and O(2)(-); NO production was confirmed by nitrite accumulation. The effects of E(2) were prevented by the antiestrogen tamoxifen and by specific kinase inhibitors, indicating a receptor-mediated mechanism and involvement of p38 MAPK and PKC. E(2) induced rapid and transient increases in the phosphorylation state of PKC, as well as of a aCREB-like (cAMP responsive element binding protein) transcription factor, as indicated by Western blot analysis with specific anti-phospho-antibodies. Localization of estrogen receptor-alpha- and -beta-like proteins in hemocytes was investigated by immunofluorescence confocal microscopy. The effects of E(2) on immune function were also investigated in vivo at 6 and 24 h in hemocytes of E(2)-injected mussels. E(2) significantly affected hemocyte lysosomal membrane stability, phagocytosis, and extracellular release of hydrolytic enzymes: lower concentrations of E(2) resulted in immunostimulation, and higher concentrations were inhibitory. Our data indicate that the physiological role of E(2) in immunomodulation is conserved from invertebrates to mammals.


Asunto(s)
Estradiol/farmacología , Hemocitos/efectos de los fármacos , Hemocitos/inmunología , Mytilus/enzimología , Mytilus/inmunología , Animales , Proteína de Unión a CREB/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Fosforilación , Proteína Quinasa C/antagonistas & inhibidores , Receptores de Estrógenos/metabolismo , Factor de Necrosis Tumoral alfa/farmacología
15.
Toxicology ; 218(1): 67-74, 2006 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-16293362

RESUMEN

Endocrine disrupting chemicals (EDCs) can behave as agonists or antagonists of several hormone receptors, thus mimicking or antagonizing the physiological activity of endogenous ligands. The involvement of estrogens in the regulation of angiogenesis has convincingly been demonstrated by a large body of experimental studies. Some polychlorobiphenyls (PCBs), considered EDCs, interact with estrogen receptors (ERs), so it is possible that these exogenous compounds affect the angiogenic process. Using fluorescence polarization, we firstly assayed whether PCB 77 (3,3',4,4'-tetrachlorobiphenyl), PCB 153 (2,2',4,4',5,5'-hexachlorobiphenyl) and PCB 156 (2,3,3',4,4',5-hexachlorobiphenyl) were able to bind to the alpha isoform of ER, recently found to be involved in angiogenesis. To discriminate the putative agonist or antagonist binding behaviour of these compounds, we tested their ability to activate, similarly to the natural ligand 17-beta-estradiol (17betaE(2)), the extracellular-signal-regulated kinase (Erk) 1/2 in human umbilical vascular endothelial (HUVE) cells. Finally, by using a new angiogenic assay, we evaluated the effect of PCBs treatment on microvessels neoformation. The data obtained in the present study showed that all the PCBs tested were able to bind to ERalpha and to elicit a response which can be agonistic or antagonistic; moreover, PCB 153 and PCB 77 can either positively or negatively modulate the angiogenic process, thus behaving as EDCs in endothelial cells.


Asunto(s)
Disruptores Endocrinos/toxicidad , Células Endoteliales/efectos de los fármacos , Receptor alfa de Estrógeno/metabolismo , Neovascularización Patológica/inducido químicamente , Bifenilos Policlorados/toxicidad , Unión Competitiva , Células Cultivadas , Disruptores Endocrinos/química , Células Endoteliales/enzimología , Células Endoteliales/metabolismo , Humanos , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Modelos Biológicos , Neovascularización Patológica/metabolismo , Bifenilos Policlorados/química , Cordón Umbilical/irrigación sanguínea , Cordón Umbilical/citología
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