RESUMEN
Cisplatin is used in the treatment of a wide variety of solid tumors, but its use is limited by its serious adverse effects, including ototoxicity. Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed serine/threonine kinase that regulates a variety of cellular functions by phosphorylating its substrates. However, the otoprotective effect of GSK-3 inhibitors is poorly understood. Here, we investigated whether GSK-3 is involved in cisplatin-induced ototoxicity in HEI-OC1 cells and organs of Corti (OCs). GSK-3 inhibitors suppressed cisplatin-induced apoptosis determined by decreased p53 activity, and also decreased expression of PARP and p53 target genes such as p21 and PUMA. The effect of GSK-3 inhibitors was mediated by markedly increased nuclear ß-catenin that in turn blocked nuclear translocation of NF-κB. siRNA-mediated ß-catenin knockdown markedly increased the expression of NF-κB target genes, such as TNF-α and IL-6. Our data suggest that the GSK-3/ß-catenin pathway may play a central role in cisplatin-mediated cytotoxicity in HEI-OC1 cells and hair cells of OCs in vitro.
Asunto(s)
Antineoplásicos/toxicidad , Cisplatino/toxicidad , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , beta Catenina/metabolismo , Animales , Apoptosis/efectos de los fármacos , Línea Celular , Citocinas/genética , Regulación de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Glucógeno Sintasa Quinasa 3/metabolismo , Interleucina-6/genética , Ratones , FN-kappa B/genética , Órgano Espiral/efectos de los fármacos , Órgano Espiral/metabolismo , ARN Interferente Pequeño/metabolismo , Ratas , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
The peroxisome is an intracellular organelle that responds dynamically to environmental changes. Various model organisms have been used to study the roles of peroxisomal proteins in maintaining cellular homeostasis. By taking advantage of the zebrafish model whose early stage of embryogenesis is dependent on yolk components, we examined the developmental roles of the D-bifunctional protein (Dbp), an essential enzyme in the peroxisomal ß-oxidation. The knockdown of dbp in zebrafish phenocopied clinical manifestations of its deficiency in human, including defective craniofacial morphogenesis, growth retardation, and abnormal neuronal development. Overexpression of murine Dbp rescued the morphological phenotypes induced by dbp knockdown, indicative of conserved roles of Dbp during zebrafish and mammalian development. Knockdown of dbp impaired normal development of blood, blood vessels, and most strikingly, endoderm-derived organs including the liver and pancreas - a phenotype not reported elsewhere in connection with peroxisome dysfunction. Taken together, our results demonstrate for the first time that zebrafish might be a useful model animal to study the role of peroxisomes during vertebrate development.
Asunto(s)
Trastorno Peroxisomal/enzimología , Proteína-2 Multifuncional Peroxisomal/genética , Proteínas de Pez Cebra/genética , Pez Cebra/genética , Secuencia de Aminoácidos , Animales , Secuencia Conservada , Modelos Animales de Enfermedad , Desarrollo Embrionario , Tracto Gastrointestinal/anomalías , Expresión Génica , Técnicas de Silenciamiento del Gen , Prueba de Complementación Genética , Humanos , Ratones , Datos de Secuencia Molecular , Neurogénesis , Trastorno Peroxisomal/genética , Proteína-2 Multifuncional Peroxisomal/metabolismo , Peroxisomas/enzimología , Saco Vitelino/metabolismo , Pez Cebra/embriología , Proteínas de Pez Cebra/metabolismoRESUMEN
Common metastatic sites of hepatocellular carcinoma include lung, peritoneum, adrenal gland and bone, but rarely, skin can be metastatic sites. Although hepatocellular carcinoma is the third commonest malignancy in Korea, cutaneous metastasis from hepatocellular carcinoma was rarely reported. Cutaneous metastasis from malignant neoplasm of the internal organ occur at the variable stage and the growth pattern of cutaneous lesions is nonspecific and various, so the differential diagnosis of skin lesions must be considered to other malignant condition. We report a case of cutaneous metastasis from recurrent hepatocellular carcinoma that was confirmed by skin biopsy with immunohistochemical stain.
