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

International Journal of Molecular Sciences

Elena Levantini¹  LuizaCoimbra Scalabrini²  DanielaSanchez Bassères²  TatianaCorrea Carneiro-Lobo²  VanessaSilva Miranda²  FelipeSilva Rodrigues²  Björn Kruspig³  DanielJ. Murphy³ 

[1] Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA;Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, 05508-000 São Paulo, Brazil;Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK;

关键词: KRAS;    lung cancer;    IKKβ kinase;    stemness;    cancer stem cells;    NF-κB signalling;   

DOI  :  10.3390/ijms21165806

来源: DOAJ

【 摘 要 】

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 β (IKKβ) to promote lung tumourigenesis, we hypothesized that inhibition of IKKβ 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 IKKβ kinase activity. IKKβ 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 IKKβ 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 IKKβ 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.

【 授权许可】

Unknown