IKK beta Kinase Promotes Stemness, Migration, and Invasion in KRAS-Driven Lung Adenocarcinoma Cells

Autor(es)

Rodrigues, Felipe Silva ^{[1, 2, 3]} ; Miranda, Vanessa Silva ^[1] ; Carneiro-Lobo, Tatiana Correa ^[1] ; Scalabrini, Luiza Coimbra ^[1] ; Kruspig, Bjorn ^[2] ; Levantini, Elena ^{[4, 5]} ; Murphy, Daniel J. ^{[2, 6]} ; Basseres, Daniela Sanchez ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Quim, Dept Bioquim, BR-05508000 Sao Paulo - Brazil

^[2] Univ Glasgow, Inst Canc Sci, Glasgow G61 1QH, Lanark - Scotland

^[3] Francis Crick Inst, Tumour Host Interact Lab, London NW1 1AT - England

^[4] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Boston, MA 02115 - USA

^[5] CNR, Ist Tecnol Biomed, I-56124 Pisa - Italy

^[6] Canc Res UK Beatson Inst, Glasgow G61 1BD, Lanark - Scotland

• Tipo de documento: Artigo Científico
• Fonte: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 21, n. 16 AUG 2020.
• Citações Web of Science: 0

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: 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: 16/22520-4 - 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
• 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: 16/19757-2 - 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