RESUMEN
AIM: The self-repair ability of neural progenitor cells (NPCs) has been found to be activated and protected in several therapies helpful in multiple sclerosis (MS), an inflammatory demyelinating disease of the CNS. As a potential therapeutic target in MS, the role of the ion channel Kv1.3 in NPC self-repair has received limited attention. The aim of this study was to explore the effects of a selective Kv1.3 blocker on NPC neuronal differentiation and maturation. METHODS: A small-molecule selective blocker for Kv1.3, Psora-4, was added to the differentiation medium of cultured mouse NPCs to assess its effect on NPC differentiation efficiency. Both a polypeptide Kv1.3 blocker and Kv1.3-specific RNA interference were used in parallel experiments. Further, the maturity of newborn neurons in the presence of Psora-4 was measured both by morphological analysis and by whole-cell patch clamping. RESULTS: Psora-4 induced a significant increase in the percentage of neurons. Knockdown of Kv1.3 in NPCs also promoted neuronal differentiation. Both morphological and electrophysiological analyses suggested that NPC-derived neurons in the presence of Psora-4 were more mature. CONCLUSION: Our studies reveal a crucial role for the ion channel Kv1.3 in the regulation of NPC differentiation and maturation, making Psora-4 a promising candidate molecule for MS treatment.
Asunto(s)
Diferenciación Celular/efectos de los fármacos , Ficusina/farmacología , Canal de Potasio Kv1.3/metabolismo , Células-Madre Neurales/efectos de los fármacos , Neurogénesis/efectos de los fármacos , Bloqueadores de los Canales de Potasio/farmacología , Análisis de Varianza , Animales , Encéfalo/citología , Proliferación Celular , Células Cultivadas , Embrión de Mamíferos , Proteína Ácida Fibrilar de la Glía/metabolismo , Canal de Potasio Kv1.3/genética , Potenciales de la Membrana/genética , Ratones , Proteínas Asociadas a Microtúbulos/metabolismo , Técnicas de Placa-Clamp , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismoRESUMEN
Aberration in cell cycle has been shown to be a common occurrence in lung cancer, and cell cycle inhibitor represents an effective therapeutic strategy. In this study, we test the effects of a natural macrocyclic depsipeptide largazole on lung cancer cells and report that this compound potently inhibits the proliferation and clonogenic activity of lung cancer cells but not normal bronchial epithelial cells. Largazole arrests cell cycle at G1 phase with up-regulation of the expression of cyclin-dependent kinase inhibitor p21. Interestingly, largazole enhances the E2F1-HDAC1 binding affinity and induces a proteasomal degradation of E2F1, leading to suppression of E2F1 function in lung cancer but not normal bronchial epithelial cells. Because E2F1 is overexpressed in lung cancer tumor samples, these data indicate that largazole is an E2F1-targeting cell cycle inhibitor, which bears therapeutic potentials for this malignant neoplasm.
