IKKβ kinase promotes stemness, migration, and invasion in KRAS-driven lung adenocarcinoma cells

Rodrigues, F. S., Miranda, V. S., Carneiro-Lobo, T. C., Scalabrini, L. C., Kruspig, B., Levantini, E., Murphy, D. J. and Bassères, D. S. (2020) IKKβ kinase promotes stemness, migration, and invasion in KRAS-driven lung adenocarcinoma cells. International Journal of Molecular Sciences, 21(16), 5806. (doi: 10.3390/ijms21165806) (PMID:32823550) (PMCID:PMC7460870)

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Abstract

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.

Item Type:Articles
Additional Information:This work was supported by a Research Grant (2016/19757-2) from the Fundação de Apoio à Pesquisa do Estado de São Paulo (FAPESP) to D.S.B., by a FAPESP postdoctoral fellowship to T.C.C.L. (2012/13774-1), by FAPESP masters fellowships to F.S.R. (2016/22520-4) and V.S.M. (2016/10404-0), a FAPESP Research Internships Abroad (BEPE) fellowship to F.S.R. (2017/22125-0) and by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Ph.D. fellowship to L.C.S. (155381/2016-4). This work was also supported by the graduate program in Biochemistry and Molecular Biology of the University of São Paulo, which is sponsored by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, PROEX 1888/2016).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Kruspig, Dr Bjorn and Murphy, Professor Daniel
Authors: Rodrigues, F. S., Miranda, V. S., Carneiro-Lobo, T. C., Scalabrini, L. C., Kruspig, B., Levantini, E., Murphy, D. J., and Bassères, D. S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:International Journal of Molecular Sciences
Publisher:MDPI
ISSN:1661-6596
ISSN (Online):1422-0067
Published Online:13 August 2020
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in International Journal of Molecular Sciences 21(16): 5806
Publisher Policy:Reproduced under a Creative Commons License

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