The specific IKKε/TBK1 inhibitor amlexanox suppresses human melanoma by the inhibition of autophagy, NF-κB and MAP kinase pathways

  • Inhibitor-kappaB kinase epsilon (IKKε) and TANK-binding kinase 1 (TBK1) are non-canonical IκB kinases, both described as contributors to tumor growth and metastasis in different cancer types. Several hints indicate that they are also involved in the pathogenesis of melanoma; however, the impact of their inhibition as a potential therapeutic measure in this “difficult-to-treat” cancer type has not been investigated so far. We assessed IKKε and TBK1 expression in human malignant melanoma cells, primary tumors and the metastasis of melanoma patients. Both kinases were expressed in the primary tumor and in metastasis and showed a significant overexpression in tumor cells in comparison to melanocytes. The pharmacological inhibition of IKKε/TBK1 by the approved drug amlexanox reduced cell proliferation, migration and invasion. Amlexanox did not affect the cell cycle progression nor apoptosis induction but significantly suppressed autophagy in melanoma cells. The analysis of potential functional downstream targets revealed that NF-кB and ERK pathways might be involved in kinase-mediated effects. In an in vivo xenograft model in nude mice, amlexanox treatment significantly reduced tumor growth. In conclusion, amlexanox was able to suppress tumor progression potentially by the inhibition of autophagy as well as NF-кB and MAP kinase pathways and might therefore constitute a promising candidate for melanoma therapy.

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Author:Moritz Möller, Julia Wasel, Julia Schmetzer, Ulrike Weiß, Markus Meissner, Susanne SchiffmannORCiDGND, Andreas Weigert, Christine Verena Möser, Ellen Niederberger
URN:urn:nbn:de:hebis:30:3-550736
DOI:https://doi.org/10.3390/ijms21134721
ISSN:1422-0067
ISSN:1661-6596
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/32630674
Parent Title (English):International journal of molecular sciences
Publisher:Molecular Diversity Preservation International
Place of publication:Basel
Document Type:Article
Language:English
Year of Completion:2020
Date of first Publication:2020/07/02
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2020/07/15
Tag:IKKε; NF-кB; TBK1; amlexanox; melanoma; tumor growth
Volume:21
Issue:13, Art. 4721
Page Number:20
First Page:1
Last Page:20
Note:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
HeBIS-PPN:467515638
Institutes:Medizin / Medizin
Fachübergreifende Einrichtungen / Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Open-Access-Publikationsfonds:Medizin
Licence (German):License LogoCreative Commons - Namensnennung 4.0