| Full text | |
| Author(s): |
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]
Total Authors: 8
|
| Affiliation: | [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
Total Affiliations: 6
|
| Document type: | Journal article |
| Source: | INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 21, n. 16 AUG 2020. |
| Web of Science Citations: | 0 |
| 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-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) | |
| FAPESP's process: | 16/10404-0 - Exploring IKKbeta as an anti-metastatic therapeutic target in KRAS-induced lung câncer |
| Grantee: | Vanessa Silva Miranda |
| Support Opportunities: | Scholarships in Brazil - Master |
| FAPESP's process: | 16/22520-4 - Exploring IKKbeta kinase as a therapeutic target for lung tumour-initiating cells induced by the KRAS oncogene |
| Grantee: | Felipe Silva Rodrigues |
| Support Opportunities: | Scholarships in Brazil - Master |
| FAPESP's process: | 12/13774-1 - THE ROLE OF THE IKKbeta KINASE IN K-RAS-INDUCED ANGIOGENESIS. |
| Grantee: | Tatiana Corrêa Carneiro Lobo |
| Support Opportunities: | Scholarships in Brazil - Post-Doctorate |
| FAPESP's process: | 16/19757-2 - EXPLORING IKKbeta KINASE AS AN ANTI-METASTATIC THERAPEUTIC TARGET IN KRAS-INDUCED LUNG CANCER |
| Grantee: | Daniela Sanchez Basseres |
| Support Opportunities: | Regular Research Grants |
| FAPESP's process: | 17/22125-0 - Investigating the role of IKKbeta kinase and ERBB in the maintenance of the cancer stem-like phenotype in KRAS-driven lung cancer |
| Grantee: | Felipe Silva Rodrigues |
| Support Opportunities: | Scholarships abroad - Research Internship - Master's degree |