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1.
Environ Toxicol Pharmacol ; 107: 104424, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38522766

RESUMEN

The role of benzo[a]pyrene (BaP), a prominent genotoxic carcinogen and aryl hydrocarbon receptor (AhR) ligand, in tumor progression remains poorly characterized. We investigated the impact of BaP on the process of epithelial-mesenchymal transition (EMT) in normal human bronchial epithelial HBEC-12KT cells. Early morphological changes after 2-week exposure were accompanied with induction of SERPINB2, IL1, CDKN1A/p21 (linked with cell cycle delay) and chemokine CXCL5. After 8-week exposure, induction of cell migration and EMT-related pattern of markers/regulators led to induction of further pro-inflammatory cytokines or non-canonical Wnt pathway ligand WNT5A. This trend of up-regulation of pro-inflammatory genes and non-canonical Wnt pathway constituents was observed also in the BaP-transformed HBEC-12KT-B1 cells. In general, transcriptional effects of BaP differed from those of TGFß1, a prototypical EMT inducer, or a model non-genotoxic AhR ligand, TCDD. Carcinogenic polycyclic aromatic hydrocarbons could thus induce a unique set of molecular changes linked with EMT and cancer progression.


Asunto(s)
Benzo(a)pireno , Células Epiteliales , Humanos , Benzo(a)pireno/toxicidad , Ligandos , Células Epiteliales/metabolismo , Daño del ADN , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo
2.
Cells ; 11(4)2022 02 17.
Artículo en Inglés | MEDLINE | ID: mdl-35203356

RESUMEN

Apart from its role in the metabolism of carcinogens, the aryl hydrocarbon receptor (AhR) has been suggested to be involved in the control of inflammatory responses within the respiratory tract. However, the mechanisms responsible for this are only partially known. In this study, we used A549 cell line, as a human model of lung alveolar type II (ATII)-like cells, to study the functional role of the AhR in control of inflammatory responses. Using IL-1ß as an inflammation inducer, we found that the induction of cyclooxygenase-2 and secretion of prostaglandins, as well as expression and release of pro-inflammatory cytokines, were significantly higher in the AhR-deficient A549 cells. This was linked with an increased nuclear factor-κB (NF-κB) activity, and significantly enhanced phosphorylation of its regulators, IKKα/ß, and their target IκBα, in the AhR-deficient A549 cells. In line with this, when we mimicked the exposure to a complex mixture of airborne pollutants, using an organic extract of reference diesel exhaust particle mixture, an exacerbated inflammatory response was observed in the AhR-deficient cells, as compared with wild-type A549 cells. Together, the present results indicate that the AhR may act as a negative regulator of the inflammatory response in the A549 model, via a direct modulation of NF-κB signaling. Its role(s) in the control of inflammation within the lung alveoli exposed to airborne pollutants, especially those which simultaneously activate the AhR, thus deserve further attention.


Asunto(s)
Contaminantes Ambientales , Inflamación , FN-kappa B , Receptores de Hidrocarburo de Aril , Células A549 , Contaminantes Ambientales/toxicidad , Humanos , Inflamación/patología , FN-kappa B/metabolismo , Receptores de Hidrocarburo de Aril/metabolismo
3.
Toxicology ; 461: 152897, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34403729

RESUMEN

Cytochrome P450 family 1 (CYP1) enzymes contribute both to metabolism of xenobiotics and to the control of endogenous levels of ligands of the aryl hydrocarbon receptor (AhR). Their activities, similar to other CYPs, can be altered in tumor tissues. Here, we examined a possible role of proliferative/survival pathways signaling, which is often deregulated in tumor cells, and possible links with p300 histone acetyltransferase (a transcriptional co-activator) in the control of CYP1 expression, focusing particularly on CYP1A1. Using cell models derived from human liver, we observed that the induction of CYP1A1 expression, as well as other CYP1 enzymes, was reduced in exponentially growing cells, as compared with their non-dividing counterparts. The siRNA-mediated inhibition of proliferation/pro-survival signaling pathway effectors (such as ß-catenin and/or Hippo pathway effectors YAP/TAZ) increased the AhR ligand-induced CYP1A1 mRNA levels in liver HepaRG cells, and/or in colon carcinoma HCT-116 cells. The activation of proliferative Wnt/ß-catenin signaling in HCT-116 cells reduced both the induction of CYP1 enzymes and the binding of p300 to the promoter of CYP1A1 or CYP1B1 genes. These results seem to indicate that aberrant proliferative signaling in tumor cells could suppress induction of CYP1A1 (or other CYP1 enzymes) via competition for p300 binding. This mechanism could be involved in modulation of the metabolism of both endogenous and exogenous substrates of CYP1A1 (and other CYP1 enzymes), with possible further consequences for alterations of the AhR signaling in tumor cells, or additional functional roles of CYP1 enzymes.


Asunto(s)
Proliferación Celular/fisiología , Neoplasias del Colon/patología , Citocromo P-450 CYP1A1/genética , Hígado/patología , Línea Celular Tumoral , Supervivencia Celular/fisiología , Neoplasias del Colon/genética , Citocromo P-450 CYP1A1/biosíntesis , Proteína p300 Asociada a E1A/metabolismo , Inducción Enzimática/fisiología , Regulación Neoplásica de la Expresión Génica , Células HCT116 , Vía de Señalización Hippo/fisiología , Humanos , Transducción de Señal/fisiología , Vía de Señalización Wnt/fisiología
4.
Toxicol Sci ; 172(2): 368-384, 2019 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-31536130

RESUMEN

The aryl hydrocarbon receptor (AhR) activation has been shown to alter proliferation, apoptosis, or differentiation of adult rat liver progenitors. Here, we investigated the impact of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated AhR activation on a human model of bipotent liver progenitors, undifferentiated HepaRG cells. We used both intact undifferentiated HepaRG cells, and the cells with silenced Hippo pathway effectors, yes-associated protein 1 (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), which play key role(s) in tissue-specific progenitor cell self-renewal and expansion, such as in liver, cardiac, or respiratory progenitors. TCDD induced cell proliferation in confluent undifferentiated HepaRG cells; however, following YAP, and, in particular, double YAP/TAZ knockdown, TCDD promoted induction of apoptosis. These results suggested that, unlike in mature hepatocytes, or hepatocyte-like cells, activation of the AhR may sensitize undifferentiated HepaRG cells to apoptotic stimuli. Induction of apoptosis in cells with silenced YAP/TAZ was associated with upregulation of death ligand TRAIL, and seemed to involve both extrinsic and mitochondrial apoptosis pathways. Global gene expression analysis further suggested that TCDD significantly altered expression of constituents and/or transcriptional targets of signaling pathways participating in control of expansion or differentiation of liver progenitors, including EGFR, Wnt/ß-catenin, or tumor growth factor-ß signaling pathways. TCDD significantly upregulated cytosolic proapoptotic protein BMF (Bcl-2 modifying factor) in HepaRG cells, which could be linked with an enhanced sensitivity of TCDD-treated cells to apoptosis. Our results suggest that, in addition to promotion of cell proliferation and alteration of signaling pathways controlling expansion of human adult liver progenitors, AhR ligands may also sensitize human liver progenitor cells to apoptosis.


Asunto(s)
Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Hígado/efectos de los fármacos , Modelos Biológicos , Dibenzodioxinas Policloradas/toxicidad , Células Madre/efectos de los fármacos , Proteínas Adaptadoras Transductoras de Señales/genética , Apoptosis/genética , Línea Celular , Proliferación Celular/genética , Expresión Génica/efectos de los fármacos , Humanos , Hígado/patología , ARN Interferente Pequeño/genética , Receptores de Hidrocarburo de Aril/metabolismo , Transducción de Señal , Células Madre/patología , Transactivadores/genética , Factores de Transcripción/genética , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ , Transfección , Proteínas Señalizadoras YAP
5.
Toxicology ; 333: 37-44, 2015 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-25843524

RESUMEN

Inhibition of apoptosis by the ligands of the aryl hydrocarbon receptor (AhR) has been proposed to play a role in their tumor promoting effects on liver parenchymal cells. However, little is presently known about the impact of toxic AhR ligands, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on apoptosis in other liver cell types, such as in liver epithelial/progenitor cells. In the present study, we focused on the effects of TCDD on apoptosis regulation in a model of liver progenitor cells, rat WB-F344 cell line, during the TCDD-elicited release from contact inhibition. The stimulation of cell proliferation in this cell line was associated with deregulated expression of a number of genes known to be under transcriptional control of the Hippo signaling pathway, a principal regulatory pathway involved in contact inhibition of cell proliferation. Interestingly, we found that mRNA and protein levels of survivin, a known Hippo target, which plays a role both in cell division and inhibition of apoptosis, were significantly up-regulated in rat liver epithelial cell model, as well as in undifferentiated human liver HepaRG cells. Using the short interfering RNA-mediated knockdown, we confirmed that survivin plays a central role in cell division of WB-F344 cells. When evaluating the effects of TCDD on apoptosis induction by camptothecin, a genotoxic topoisomerase I inhibitor, we observed that the pre-treatment of WB-F344 cells with TCDD increased number of cells with apoptotic nuclear morphology, and it potentiated cleavage of both caspase-3 and poly(ADP-ribose) polymerase I. This indicated that despite the observed up-regulation of survivin, apoptosis induced by the genotoxin was potentiated in the model of rat liver progenitor cells. The present results indicate that, unlike in hepatocytes, AhR agonists may not prevent induction of apoptosis elicited by DNA-damaging agents in a model of rat liver progenitor cells.


Asunto(s)
Apoptosis/efectos de los fármacos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/agonistas , Camptotecina/toxicidad , Inhibición de Contacto/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Hígado/efectos de los fármacos , Proteínas Asociadas a Microtúbulos/metabolismo , Dibenzodioxinas Policloradas/toxicidad , Receptores de Hidrocarburo de Aril/agonistas , Inhibidores de Topoisomerasa I/toxicidad , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Caspasa 3/metabolismo , Línea Celular , Células Epiteliales/metabolismo , Células Epiteliales/patología , Humanos , Proteínas Inhibidoras de la Apoptosis/genética , Proteínas Inhibidoras de la Apoptosis/metabolismo , Hígado/metabolismo , Hígado/patología , Proteínas Asociadas a Microtúbulos/genética , Poli(ADP-Ribosa) Polimerasa-1 , Poli(ADP-Ribosa) Polimerasas/metabolismo , Interferencia de ARN , Ratas Endogámicas F344 , Receptores de Hidrocarburo de Aril/metabolismo , Transducción de Señal/efectos de los fármacos , Survivin , Factores de Tiempo , Transcripción Genética/efectos de los fármacos , Transfección , Regulación hacia Arriba
6.
Mutagenesis ; 30(4): 565-76, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25805023

RESUMEN

Deregulation of Wnt/ß-catenin signalling plays an important role in the pathogenesis of colorectal cancer. Interestingly, this pathway has been recently implicated in transcriptional control of cytochrome P450 (CYP) family 1 enzymes, which are responsible for bioactivation of a number of dietary carcinogens. In the present study, we investigated the impact of inhibition of Wnt/ß-catenin pathway on metabolism and genotoxicity of benzo[a]pyrene (BaP), a highly mutagenic polycyclic aromatic hydrocarbon and an efficient ligand of the aryl hydrocarbon receptor, which is known as a primary regulator of CYP1 expression, in cellular models derived from colorectal tumours. We observed that a synthetic inhibitor of ß-catenin, JW74, significantly increased formation of BaP-induced DNA adducts in both colorectal adenoma and carcinoma-derived cell lines. Using the short interfering RNA (siRNA) targeting ß-catenin, we then found that ß-catenin knockdown in HCT116 colon carcinoma cells significantly enhanced formation of covalent DNA adducts by BaP and histone H2AX phosphorylation, as detected by (32)P-postlabelling technique and immunocytochemistry, respectively, and it also induced expression of DNA damage response genes, such as CDKN1A or DDB2. The increased formation of DNA adducts formed by BaP upon ß-catenin knockdown corresponded with enhanced production of major BaP metabolites, as well as with an increased expression/activity of CYP1 enzymes. Finally, using siRNA-mediated knockdown of CYP1A1, we confirmed that this enzyme plays a major role in formation of BaP-induced DNA adducts in HCT116 cells. Taken together, the present results indicated that the siRNA-mediated inhibition of ß-catenin signalling, which is aberrantly activated in a majority of colorectal cancers, modulated genotoxicity of dietary carcinogen BaP in colon cell model in vitro, via a mechanism involving up-regulation of CYP1 expression and activity.


Asunto(s)
Benzo(a)pireno/efectos adversos , Neoplasias del Colon/etiología , Neoplasias del Colon/patología , Citocromo P-450 CYP1A1/metabolismo , Aductos de ADN/efectos adversos , Daño del ADN , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , beta Catenina/antagonistas & inhibidores , Apoptosis , Western Blotting , Carcinógenos Ambientales/efectos adversos , Proliferación Celular , Neoplasias del Colon/tratamiento farmacológico , Citocromo P-450 CYP1A1/antagonistas & inhibidores , Citocromo P-450 CYP1A1/genética , Humanos , Técnicas para Inmunoenzimas , ARN Mensajero/genética , ARN Interferente Pequeño/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales Cultivadas , beta Catenina/genética , beta Catenina/metabolismo
7.
Toxicol Lett ; 232(1): 113-21, 2015 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-25268939

RESUMEN

Polycyclic aromatic hydrocarbons (PAHs) with lower molecular weight exhibit lesser genotoxicity and carcinogenicity than highly carcinogenic PAHs with a higher number of benzene rings. Nevertheless, they elicit specific effects linked with tumor promotion, such as acute inhibition of gap junctional intercellular communication (GJIC). Although inflammatory reaction may alter bioactivation and toxicity of carcinogenic PAHs, little is known about the impact of pro-inflammatory cytokines on toxic effects of the low-molecular-weight PAHs. Here, we investigated the impact of a pro-inflammatory cytokine, tumor necrosis factor-α (TNF-α), on the effects associated with tumor promotion and with induction of the aryl hydrocarbon receptor (AhR)-dependent gene expression in rat liver epithelial cells. We found that a prolonged incubation with TNF-α induced a down-regulation of GJIC, associated with reduced expression of connexin 43 (Cx43), a major connexin isoform found in liver epithelial cells. The Cx43 down-regulation was partly mediated by the activity of the mitogen-activated protein (MAP) p38 kinase. Independently of GJIC modulation, or p38 activation, TNF-α potentiated the AhR-dependent proliferative effect of a model low-molecular-weight PAH, fluoranthene, on contact-inhibited cells. In contrast, this pro-inflammatory cytokine repressed the fluoranthene-induced expression of a majority of model AhR gene targets, such as Cyp1a1, Ahrr or Tiparp. The results of the present study indicate that inflammatory reaction may differentially modulate various toxic effects of low-molecular-weight PAHs; the exposure to pro-inflammatory cytokines may both strengthen (inhibition of GJIC, disruption of contact inhibition) and repress (expression of a majority of AhR-dependent genes) their impact on toxic endpoints associated with carcinogenesis.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/agonistas , Comunicación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Fluorenos/toxicidad , Uniones Comunicantes/efectos de los fármacos , Hígado/efectos de los fármacos , Receptores de Hidrocarburo de Aril/agonistas , Transcripción Genética/efectos de los fármacos , Factor de Necrosis Tumoral alfa/toxicidad , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Línea Celular , Transformación Celular Neoplásica/inducido químicamente , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Conexina 43/genética , Conexina 43/metabolismo , Relación Dosis-Respuesta a Droga , Activación Enzimática , Células Epiteliales/metabolismo , Células Epiteliales/patología , Uniones Comunicantes/metabolismo , Uniones Comunicantes/patología , Regulación de la Expresión Génica/efectos de los fármacos , Inflamación/inducido químicamente , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Hígado/metabolismo , Hígado/patología , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Peso Molecular , Ratas , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
8.
Carcinogenesis ; 35(11): 2534-43, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25233930

RESUMEN

Cytochrome P450 1B1 (CYP1B1) is an enzyme that has a unique tumor-specific pattern of expression and is capable of bioactivating a wide range of carcinogenic compounds. We have reported previously that coordinated upregulation of CYP1B1 by inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and the aryl hydrocarbon receptor ligands, may increase bioactivation of promutagens, such as benzo[a]pyrene (BaP) in epithelial cells. Here, we extend those studies by describing a novel mechanism participating in the regulation of CYP1B1 expression, which involves activation of the p38 mitogen-activated protein kinase (p38) and mitogen- and stress-activated protein kinase 1 (MSK1). Using inhibitors of p38 and MSKs, as well as mouse embryonic cells derived from p38α-deficient and MSK1/2 double knockout mice, we show here that TNF-α potentiates CYP1B1 upregulation via the p38/MSK1 kinase cascade. Effects of this inflammatory cytokine on CYP1B1 expression further involve the positive transcription elongation factor b (P-TEFb). The inhibition of the P-TEFb subunit, cyclin-dependent kinase 9 (CDK9), which phosphorylates RNA polymerase II (RNAPII), prevented the enhanced CYP1B1 induction by a combination of BaP and inflammatory cytokine. Furthermore, using chromatin immunoprecipitation assays, we found that cotreatment of epithelial cells with TNF-α and BaP resulted in enhanced recruitment of both CDK9 and RNAPII to the Cyp1b1 gene promoter. Overall, these results have implications concerning the contribution of inflammatory factors to carcinogenesis, since enhanced CYP1B1 induction during inflammation may alter metabolism of exogenous carcinogens, as well as endogenous CYP1B1 substrates playing role in tumor development.


Asunto(s)
Carcinogénesis/genética , Citocromo P-450 CYP1B1/biosíntesis , Neoplasias/genética , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Animales , Carcinogénesis/efectos de los fármacos , Carcinógenos/toxicidad , Quinasa 9 Dependiente de la Ciclina/genética , Citocromo P-450 CYP1B1/genética , Citocinas/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Neoplasias/inducido químicamente , Neoplasias/patología , Factor B de Elongación Transcripcional Positiva/genética , ARN Polimerasa II/genética , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
9.
Toxicol Sci ; 134(2): 258-70, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23690540

RESUMEN

Plakoglobin is an important component of intercellular junctions, including both desmosomes and adherens junctions, which is known as a tumor suppressor. Although mutations in the plakoglobin gene (Jup) and/or changes in its protein levels have been observed in various disease states, including cancer progression or cardiovascular defects, the information about endogenous or exogenous stimuli orchestrating Jup expression is limited. Here we show that the aryl hydrocarbon receptor (AhR) may regulate Jup expression in a cell-specific manner. We observed a significant suppressive effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a model toxic exogenous activator of the AhR signaling, on Jup expression in a variety of experimental models derived from rodent tissues, including contact-inhibited rat liver progenitor cells (where TCDD induces cell proliferation), rat and mouse hepatoma cell models (where TCDD inhibits cell cycle progression), cardiac cells derived from the mouse embryonic stem cells, or cardiomyocytes isolated from neonatal rat hearts. The small interfering RNA (siRNA)-mediated knockdown of AhR confirmed its role in both basal and TCDD-deregulated Jup expression. The analysis of genomic DNA located ~2.5kb upstream of rat Jup gene revealed a presence of evolutionarily conserved AhR binding motifs, which were confirmed upon their cloning into luciferase reporter construct. The siRNA-mediated knockdown of Jup expression affected both proliferation and attachment of liver progenitor cells. The present data indicate that the AhR may contribute to negative regulation of Jup gene expression in rodent cellular models, which may affect cell adherence and proliferation.


Asunto(s)
Regulación de la Expresión Génica/fisiología , Receptores de Hidrocarburo de Aril/fisiología , gamma Catenina/genética , Animales , Secuencia de Bases , Adhesión Celular , Línea Celular , Proliferación Celular , Clonación Molecular , Cartilla de ADN , Regulación hacia Abajo , Dibenzodioxinas Policloradas/farmacología , Regiones Promotoras Genéticas , Ratas , Ratas Endogámicas F344 , Reacción en Cadena en Tiempo Real de la Polimerasa
10.
Arch Toxicol ; 87(3): 491-503, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23085979

RESUMEN

The aryl hydrocarbon receptor (AhR) contributes to the control of cell-to-cell communication, cell adhesion, migration or proliferation. In the present study, we investigated the regulation of connexin43 (Cx43) and Cx43-mediated gap junctional intercellular communication (GJIC) during the AhR-dependent disruption of contact inhibition in non-tumorigenic liver epithelial cells. The contact inhibition of cell proliferation is a process restricting the cell division of confluent non-transformed cells, which is frequently abolished in cancer cells; however, the mechanisms contributing to its disruption are still only partially understood. Disruption of contact inhibition, which was induced by toxic AhR ligands 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or polycyclic aromatic hydrocarbons in epithelial WB-F344 cells, reduced Cx43 protein levels, possibly via enhanced proteasomal degradation, significantly decreased the amount of gap junction plaques and downregulated GJIC, in an AhR-dependent manner. Although both intracellular and membrane Cx43 pools were markedly reduced in cells released from contact inhibition by TCDD, siRNA-mediated Cx43 knock-down was not sufficient to stimulate proliferation in contact-inhibited cells. Our data suggest that downregulation of Cx43/GJIC in non-transformed epithelial cells is an inherent part of disruption of contact inhibition, which occurs at the post-transcriptional level. This process runs in parallel with alterations of other forms of cell-to-cell communication, thus suggesting that toxic AhR agonists may simultaneously abrogate contact inhibition and reduce GJIC, two essential mechanisms linked to deregulation of cell-to-cell communication during tumor promotion and progression.


Asunto(s)
Carcinógenos/toxicidad , Comunicación Celular/efectos de los fármacos , Conexina 43/metabolismo , Inhibición de Contacto/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Uniones Comunicantes/efectos de los fármacos , Hígado/efectos de los fármacos , Receptores de Hidrocarburo de Aril/agonistas , Transducción de Señal/efectos de los fármacos , Animales , Benzo(a)Antracenos/toxicidad , Línea Celular , Proliferación Celular , Transformación Celular Neoplásica/inducido químicamente , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Conexina 43/genética , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo , Células Epiteliales/metabolismo , Células Epiteliales/patología , Fluorenos/toxicidad , Uniones Comunicantes/metabolismo , Uniones Comunicantes/patología , Técnicas de Silenciamiento del Gen , Indoles/farmacología , Ligandos , Hígado/metabolismo , Hígado/patología , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Floroglucinol/análogos & derivados , Floroglucinol/farmacología , Fosforilación , Dibenzodioxinas Policloradas/toxicidad , Complejo de la Endopetidasa Proteasomal/metabolismo , Interferencia de ARN , Ratas , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Factores de Tiempo , Transfección
11.
Cell Signal ; 24(8): 1665-76, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22560882

RESUMEN

Crosstalk between the aryl hydrocarbon receptor (AhR) and transforming growth factor-ß1 (TGF-ß1) signaling has been observed in various experimental models. However, both molecular mechanism underlying this crosstalk and tissue-specific context of this interaction are still only partially understood. In a model of human non-tumorigenic prostate epithelial cells BPH-1, derived from the benign prostatic hyperplasia, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) persistently activates the AhR signaling pathway and induces expression of xenobiotic metabolizing enzymes, such as CYP1A1 or CYP1B1. Here we demonstrate that TGF-ß1 suppresses the AhR-mediated gene expression through multiple mechanisms, involving inhibition of AhR expression and down-regulation of nuclear AhR, via a SMAD4-dependent pathway. In contrast, TCDD-induced AhR signaling does not affect either TGF-ß1-regulated gene expression or epithelial-to-mesenchymal transition. These observations suggest that, in the context of prostate epithelium, TGF-ß1 signaling plays a dominant role in the crosstalk with AhR signaling pathway. Given the importance of TGF-ß1 signaling in regulation of prostate epithelial tissue homeostasis, as well as the recently revealed role of AhR in prostate development and tumorigenesis, the above findings contribute to our understanding of the mechanisms underlying the crosstalk between the two signaling pathways in the prostate-specific context.


Asunto(s)
Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Dibenzodioxinas Policloradas/farmacología , Próstata/citología , Transducción de Señal/efectos de los fármacos , Factor de Crecimiento Transformador beta1/metabolismo , Células Cultivadas , Humanos , Ligandos , Masculino , Receptores de Hidrocarburo de Aril/antagonistas & inhibidores , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Proteínas Recombinantes/metabolismo , Factor de Crecimiento Transformador beta1/genética
12.
Toxicol Sci ; 122(2): 349-60, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21602191

RESUMEN

ß-catenin is a key integrator of cadherin-mediated cell-cell adhesion and transcriptional regulation through the Wnt/ß-catenin pathway, which plays an important role in liver biology. Using a model of contact-inhibited liver progenitor cells, we examined the interactions of Wnt/ß-catenin signaling with the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, which mediates the toxicity of dioxin-like compounds, including their effects on development and hepatocarcinogenesis. We found that AhR and Wnt/ß-catenin cooperated in the induction of AhR transcriptional targets, such as Cyp1a1 and Cyp1b1. However, simultaneously, the activation of AhR led to a decrease of dephosphorylated active ß-catenin pool, as well as to hypophosphorylation of Dishevelled, participating in regulation of Wnt signaling. A sustained AhR activation by its model ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), led to a downregulation of a number of Wnt/ß-catenin pathway target genes. TCDD also induced a switch in cytokeratin expression, where downregulation of cytokeratins 14 and 19 was accompanied with an increased cytokeratin 8 expression. Together with a downregulation of additional markers associated with stem-like phenotype, this indicated that the AhR activation interfered with differentiation of liver progenitors. The downregulation of ß-catenin was also related to a reduced cell adhesion, disruption of E-cadherin-mediated cell-cell junctions and an increased G1-S transition in liver progenitor cell line. In conclusion, although ß-catenin augmented the expression of selected AhR target genes, the persistent AhR activation may lead to downregulation of Wnt/ß-catenin signaling, thus altering differentiation and/or proliferative status of liver progenitor cells.


Asunto(s)
Hígado/efectos de los fármacos , Receptores de Hidrocarburo de Aril/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animales , Hidrocarburo de Aril Hidroxilasas/genética , Hidrocarburo de Aril Hidroxilasas/metabolismo , Cadherinas/genética , Adhesión Celular , Diferenciación Celular , Línea Celular , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1B1 , Regulación hacia Abajo/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Dibenzodioxinas Policloradas/toxicidad , Ratas , Ratas Endogámicas F344 , Receptores de Hidrocarburo de Aril/genética , Proteínas Wnt/genética , Vía de Señalización Wnt , beta Catenina/genética
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