IKKβ targeting reduces KRAS-induced lung cancer angiogenesis in vitro and in vivo: A potential anti-angiogenic therapeutic target.

Autor: Carneiro-Lobo TC; Chemistry Institute, Department of Biochemistry, University of São Paulo, São Paulo, Brazil., Scalabrini LC; Chemistry Institute, Department of Biochemistry, University of São Paulo, São Paulo, Brazil., Magalhães LDS; Chemistry Institute, Department of Biochemistry, University of São Paulo, São Paulo, Brazil., Cardeal LB; Chemistry Institute, Department of Biochemistry, University of São Paulo, São Paulo, Brazil., Rodrigues FS; Chemistry Institute, Department of Biochemistry, University of São Paulo, São Paulo, Brazil., Dos Santos EO; Chemistry Institute, Department of Biochemistry, University of São Paulo, São Paulo, Brazil., Baldwin AS; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Levantini E; Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Institute of Biomedical Technologies, National Research Council (CNR), Pisa, Italy., Giordano RJ; Chemistry Institute, Department of Biochemistry, University of São Paulo, São Paulo, Brazil., Bassères DS; Chemistry Institute, Department of Biochemistry, University of São Paulo, São Paulo, Brazil. Electronic address: basseres@iq.usp.br.
Jazyk: angličtina
Zdroj: Lung cancer (Amsterdam, Netherlands) [Lung Cancer] 2019 Apr; Vol. 130, pp. 169-178. Date of Electronic Publication: 2019 Feb 25.
DOI: 10.1016/j.lungcan.2019.02.027
Abstrakt: Objectives: The ability of tumor cells to drive angiogenesis is an important cancer hallmark that positively correlates with metastatic potential and poor prognosis. Therefore, targeting angiogenesis is a rational therapeutic approach and dissecting proangiogenic pathways is important, particularly for malignancies driven by oncogenic KRAS, which are widespread and lack effective targeted therapies. Based on published studies showing that oncogenic RAS promotes angiogenesis by upregulating the proangiogenic NF-κB target genes IL-8 and VEGF, that NF-κB activation by KRAS requires the IKKβ kinase, and that targeting IKKβ reduces KRAS-induced lung tumor growth in vivo, but has limited effects on cell growth in vitro, we hypothesized that IKKβ targeting would reduce lung tumor growth by inhibiting KRAS-induced angiogenesis.
Materials and Methods: To test this hypothesis, we targeted IKKβ in KRAS-mutant lung cancer cell lines either by siRNA-mediated transfection or by treatment with Compound A (CmpdA), a highly specific IKKβ inhibitor, and used in vitro and in vivo assays to evaluate angiogenesis.
Results and Conclusions: Both pharmacological and siRNA-mediated IKKβ targeting in lung cells reduced expression and secretion of NF-κB-regulated proangiogenic factors IL-8 and VEGF. Moreover, conditioned media from IKKβ-targeted lung cells reduced human umbilical vein endothelial cell (HUVEC) migration, invasion and tube formation in vitro. Furthermore, siRNA-mediated IKKβ inhibition reduced xenograft tumor growth and vascularity in vivo. Finally, IKKβ inhibition also affects endothelial cell function in a cancer-independent manner, as IKKβ inhibition reduced pathological retinal angiogenesis in a mouse model of oxygen-induced retinopathy. Taken together, these results provide a novel mechanistic understanding of how the IKKβ pathway affects human lung tumorigenesis, indicating that IKKβ promotes KRAS-induced angiogenesis both by cancer cell-intrinsic and cancer cell-independent mechanisms, which strongly suggests IKKβ inhibition as a promising antiangiogenic approach to be explored for KRAS-induced lung cancer therapy.
(Copyright © 2019 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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