| Texto completo | |
| Autor(es): |
Rodrigues, Felipe Silva
;
Miranda, Vanessa Silva
;
Carneiro-Lobo, Tatiana Correa
;
Scalabrini, Luiza Coimbra
;
Kruspig, Bjorn
;
Levantini, Elena
;
Murphy, Daniel J.
;
Basseres, Daniela Sanchez
Número total de Autores: 8
|
| Tipo de documento: | Artigo Científico |
| Fonte: | INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 21, n. 16, p. 19-pg., 2020-08-01. |
| Resumo | |
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-kappa B) through inhibitor of nuclear factor kappa-B kinase beta (IKK beta) to promote lung tumourigenesis, we hypothesized that inhibition of IKK beta 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 IKK beta kinase activity. IKK beta 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 IKK beta 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 IKK beta 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. (AU) | |
| Processo FAPESP: | 12/13774-1 - O PAPEL DA QUINASE IKKbeta NA ANGIOGÊNESE INDUZIDA PELO ONCOGENE K-RAS. |
| Beneficiário: | Tatiana Corrêa Carneiro Lobo |
| Modalidade de apoio: | Bolsas no Brasil - Pós-Doutorado |
| Processo FAPESP: | 16/10404-0 - Investigação da quinase IKKbeta como um alvo terapêutico anti-metastático em câncer de pulmão associado a ativação do oncogene KRAS |
| Beneficiário: | Vanessa Silva Miranda |
| Modalidade de apoio: | Bolsas no Brasil - Mestrado |
| Processo FAPESP: | 16/19757-2 - EXPLORANDO A QUINASE IKKbeta COMO UM ALVO TERAPÊUTICO ANTI-METASTÁTICO NO CÂNCER DE PULMÃO INDUZIDO PELO ONCOGENE KRAS |
| Beneficiário: | Daniela Sanchez Basseres |
| Modalidade de apoio: | Auxílio à Pesquisa - Regular |
| Processo FAPESP: | 17/22125-0 - Investigando o papel da quinase IKKbeta e ERBB na manutenção do fenótipo tronco-tumoral em câncer de pulmão induzido por KRAS |
| Beneficiário: | Felipe Silva Rodrigues |
| Modalidade de apoio: | Bolsas no Exterior - Estágio de Pesquisa - Mestrado |
| Processo FAPESP: | 16/22520-4 - Explorando a quinase IKKbeta como um alvo terapêutico para células iniciadoras de tumor pulmonares induzidas pelo oncogene KRAS |
| Beneficiário: | Felipe Silva Rodrigues |
| Modalidade de apoio: | Bolsas no Brasil - Mestrado |