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Int J Mol Sci ; 21(16)2020 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-32823550

RESUMEN

KRAS oncogenic mutations are widespread in lung cancer and, because direct targeting of KRAS has proven to be challenging, KRAS-driven cancers lack effective therapies. One alternative strategy for developing KRAS targeted therapies is to identify downstream targets involved in promoting important malignant features, such as the acquisition of a cancer stem-like and metastatic phenotype. Based on previous studies showing that KRAS activates nuclear factor kappa-B (NF-κB) through inhibitor of nuclear factor kappa-B kinase ß (IKKß) to promote lung tumourigenesis, we hypothesized that inhibition of IKKß would reduce stemness, migration and invasion of KRAS-mutant human lung cancer cells. We show that KRAS-driven lung tumoursphere-derived cells exhibit stemness features and increased IKKß kinase activity. IKKß targeting by different approaches reduces the expression of stemness-associated genes, tumoursphere formation, and self-renewal, and preferentially impairs the proliferation of KRAS-driven lung tumoursphere-derived cells. Moreover, we show that IKKß targeting reduces tumour cell migration and invasion, potentially by regulating both expression and activity of matrix metalloproteinase 2 (MMP2). In conclusion, our results indicate that IKKß is an important mediator of KRAS-induced stemness and invasive features in lung cancer, and, therefore, might constitute a promising strategy to lower recurrence rates, reduce metastatic dissemination, and improve survival of lung cancer patients with KRAS-driven disease.


Asunto(s)
Adenocarcinoma del Pulmón/enzimología , Adenocarcinoma del Pulmón/patología , Movimiento Celular , Quinasa I-kappa B/metabolismo , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/patología , Células Madre Neoplásicas/patología , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Adenocarcinoma del Pulmón/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Autorrenovación de las Células/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Mutación/genética , Invasividad Neoplásica , Células Madre Neoplásicas/metabolismo , ARN Interferente Pequeño/metabolismo , Esferoides Celulares/patología
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