RESUMEN
During the second half of the last century, the prevalent knowledge recognized the voltage-gated sodium channels (VGSCs) as the proteins responsible for the generation and propagation of action potentials in excitable cells. However, over the last 25 years, new non-canonical roles of VGSCs in cancer hallmarks have been uncovered. Their dysregulated expression and activity have been associated with aggressive features and cancer progression towards metastatic stages, suggesting the potential use of VGSCs as cancer markers and prognostic factors. Recent work has elicited essential information about the signalling pathways modulated by these channels: coupling membrane activity to transcriptional regulation pathways, intracellular and extracellular pH regulation, invadopodia maturation, and proteolytic activity. In a promising scenario, the inhibition of VGSCs with FDA-approved drugs as well as with new synthetic compounds, reduces cancer cell invasion in vitro and cancer progression in vivo. The purpose of this review is to present an update regarding recent advances and ongoing efforts to have a better understanding of molecular and cellular mechanisms on the involvement of both pore-forming α and auxiliary ß subunits of VGSCs in the metastatic processes, with the aim at proposing VGSCs as new oncological markers and targets for anticancer treatments.
RESUMEN
NaV channels expression have been reported in upper airways and tracheal smooth muscle cells controlling the generation and propagation of action potentials in the respiratory tract sensory neurons, but information about the presence of these proteins in the bronchioalveolar structures in human lungs was missing. The main objective covered in this work was to determine whether the NaV1.7 channels are expressed in lower airways, and to identify the cellular identities expressing these proteins. We detected high levels of the mRNA coding for NaV1.7 channels in isolated lung fibroblasts obtained from both normal lungs, and fibrotic lungs of patients with respiratory diseases. The protein was detected with two different antibodies in the bronchioalveolar tissue, alveolar endothelium, and capillary endothelium, in normal and pathologic lungs. These evidences are useful in the dissection of molecular mechanisms of pulmonary pathologies, and lead to consider the NaV1.7 channels as potential therapeutic targets for the treatment of pulmonary diseases.
Asunto(s)
Pulmón , Células Receptoras Sensoriales , Humanos , Potenciales de Acción/fisiología , TráqueaRESUMEN
OBJECTIVES: Lung metastasizing leiomyomatosis (LML) is an infrequently diagnosed pathology developed after sexual maturation, commonly preceded by uterine myomas. Symptoms can include difficulties to breathe, cough, dyspnea and pain, because of mechanical obstruction exerted by expanding local growing leiomyomas. Lung leiomyomas are normally detected by imaging studies, but nowadays the precise diagnosis demands histological characterization of biopsies obtained from the affected tissues. The purpose of the present study was to determine the presence of genomic alterations in circulating cells of LML. METHODS: Immunohistochemical characterization of a lung biopsy extracted by thoracoscopy was performed. Pathologic proliferative smooth muscle cells were observed in a major lung metastasizing nodule, with a growing pattern similar to a uterine myoma. The presence of cellular linages different to smooth muscle cells was discarded by testing the presence of a battery of molecular markers. Also, a normal karyotype was determine by GTG-banding cytogenetic study, but a high density microarray analysis revealed six submicroscopic chromosomal regions displaying genomic abnormalities: microduplications were detected on chromosomes 4, 14, 17 and 22; and microdeletions on chromosomes 8 and 10. CONCLUSION: This study remarks the relevance of submicroscopic chromosomal analysis of unusual pathologic conditions such as Benign Metastasizing Leiomyomatosis. This propitiate a better understanding of the molecular basis on the development of the pathology, in order to reckon on minimally invasive diagnostic methods, and to design appropriate treatments.
Asunto(s)
Variaciones en el Número de Copia de ADN/genética , Genómica/métodos , Leiomiomatosis/genética , Neoplasias Pulmonares/patología , Adulto , Epigenómica , Femenino , Humanos , Cariotipo , Leiomiomatosis/diagnóstico por imagen , Leiomiomatosis/patología , Leiomiomatosis/cirugía , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/cirugía , Mioma/complicaciones , Mioma/patología , Mioma/cirugía , Metástasis de la Neoplasia/patología , Neoplasias/etiología , Neoplasias/genética , Neoplasias/patología , Células Neoplásicas Circulantes/metabolismo , Factores de Riesgo , Toracoscopía/métodos , Tomografía Computarizada por Rayos X/métodos , Neoplasias Uterinas/genética , Neoplasias Uterinas/patología , Neoplasias Uterinas/secundarioRESUMEN
Melatonin, a hormone known for its effects on free radical scavenging and antioxidant activity, can reduce lead toxicity in vivo and in vitro.We examined the effects of melatonin on lead bio-distribution. Rats were intraperitoneally injected with lead acetate (10, 15 or 20mg/kg/day) with or without melatonin (10mg/kg/day) daily for 10 days. In rats intoxicated with the highest lead doses, those treated with melatonin had lower lead levels in blood and higher levels in urine and feces than those treated with lead alone, suggesting that melatonin increases lead excretion. To explore the mechanism underlying this effect, we first assessed whether lead/melatonin complexes were formed directly. Electronic density functional (DFT) calculations showed that a lead/melatonin complex is energetically feasible; however, UV spectroscopy and NMR analysis showed no evidence of such complexes. Next, we examined the liver mRNA levels of metallothioneins (MT) 1 and 2. Melatonin cotreatment increased the MT2 mRNA expression in the liver of rats that received the highest doses of lead. The potential effects of MTs on the tissue distribution and excretion of lead are not well understood. This is the first report to suggest that melatonin directly affects lead levels in organisms exposed to subacute lead intoxication.
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Huesos/metabolismo , Encéfalo/metabolismo , Depuradores de Radicales Libres/farmacología , Plomo/metabolismo , Melatonina/farmacología , Animales , Huesos/efectos de los fármacos , Encéfalo/efectos de los fármacos , Riñón/efectos de los fármacos , Riñón/metabolismo , Plomo/sangre , Plomo/orina , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Metalotioneína/metabolismo , Ratas , Ratas Wistar , Distribución TisularRESUMEN
Functional activity of voltage-gated sodium channels (VGSC) has been associated to the invasion and metastasis behaviors of prostate, breast and some other types of cancer. We previously reported the functional expression of VGSC in primary cultures and biopsies derived from cervical cancer (CaC). Here, we investigate the relative expression levels of VGSC subunits and its possible role in CaC. Quantitative real-time PCR revealed that mRNA levels of Na(V) 1.6 α-subunit in CaC samples were â¼40-fold higher than in noncancerous cervical (NCC) biopsies. A Na(V) 1.7 α-subunit variant also showed increased mRNA levels in CaC (â¼20-fold). All four Na(V) ß subunits were also detected in CaC samples, being Na(V) ß1 the most abundant. Proteins of Na(V) 1.6 and Na(V) 1.7 α-subunits were immunolocalized in both NCC and CaC biopsies and in CaC primary cultures as well; however, although in NCC sections proteins were mainly relegated to the plasma membrane, in CaC biopsies and primary cultures the respective signal was stronger and widely distributed in both cytoplasm and plasma membrane. Functional activity of Na(V) 1.6 channels in the plasma membrane of CaC cells was confirmed by whole-cell patch-clamp experiments using Cn2, a Na(V) 1.6-specific toxin, which blocked â¼30% of the total sodium current. Blocking of sodium channels VGSC with tetrodotoxin and Cn2 did not affect proliferation neither migration, but reduced by â¼20% the invasiveness of CaC primary culture cells in vitro assays. We conclude that Na(V) 1.6 is upregulated in CaC and could serve as a novel molecular marker for the metastatic behavior of this carcinoma.
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Regulación Neoplásica de la Expresión Génica , Proteínas del Tejido Nervioso/metabolismo , Canales de Sodio/metabolismo , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Canal de Sodio Activado por Voltaje NAV1.6 , Canal de Sodio Activado por Voltaje NAV1.7 , Invasividad Neoplásica , Metástasis de la Neoplasia , Proteínas del Tejido Nervioso/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Bloqueadores de los Canales de Sodio/farmacología , Canales de Sodio/genética , Tetrodotoxina/farmacología , Neoplasias del Cuello Uterino/genética , Subunidad beta-1 de Canal de Sodio Activado por VoltajeRESUMEN
The functional expression of voltage-gated sodium channels (Na(v)) in cancer cells is associated with an increase of metastatic potential. The activity of Na(v) channels modulates different cellular processes related to the development of the malignant phenotype, such as adhesion, galvanotaxis, motility and invasiveness. Among the great diversity of cancerous phenotypes, Na(v) channels expression is common in highly metastatic cells with their distribution following a primary tumor-specific pattern. The purpose of this paper is to review the literature, regarding to: the types of Na(v) channels expressed by different types of cancer cells, the cancer cellular processes in which they play important roles, and the molecular mechanisms by which these channels promote metastasis.