TY  - JOUR
A1  - Möller, Moritz
A1  - Wasel, Julia
A1  - Schmetzer, Julia
A1  - Weiß, Ulrike
A1  - Meissner, Markus
A1  - Schiffmann, Susanne
A1  - Weigert, Andreas
A1  - Möser, Christine Verena
A1  - Niederberger, Ellen
T1  - The specific IKKε/TBK1 inhibitor amlexanox suppresses human melanoma by the inhibition of autophagy, NF-κB and MAP kinase pathways
T2  - International journal of molecular sciences
N2  - 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.
KW  - melanoma
KW  - IKKε
KW  - TBK1
KW  - amlexanox
KW  - tumor growth
KW  - NF-кB
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/55073
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-550736
SN  - 1422-0067
SN  - 1661-6596
N1  - 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
VL  - 21
IS  - 13, Art. 4721
SP  - 1
EP  - 20
PB  - Molecular Diversity Preservation International
CY  - Basel
ER  -