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Article

The Specific IKKε/TBK1 Inhibitor Amlexanox Suppresses Human Melanoma by the Inhibition of Autophagy, NF-κB and MAP Kinase Pathways

1
Pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Faculty of Medicine, Goethe-University Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany
2
Department of Dermatology, Venereology and Allergology, Faculty of Medicine, Goethe-University Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt, Germany
3
Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Branch for Translational Medicine and Pharmacology TMP, Theodor Stern-Kai 7, 60590 Frankfurt am Main, Germany
4
Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(13), 4721; https://doi.org/10.3390/ijms21134721
Received: 5 June 2020 / Revised: 29 June 2020 / Accepted: 30 June 2020 / Published: 2 July 2020
(This article belongs to the Special Issue Kinase Signal Transduction 2020)
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. View Full-Text
Keywords: melanoma; IKKε; TBK1; amlexanox; tumor growth; NF-кB melanoma; IKKε; TBK1; amlexanox; tumor growth; NF-кB
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MDPI and ACS Style

Möller, M.; Wasel, J.; Schmetzer, J.; Weiß, U.; Meissner, M.; Schiffmann, S.; Weigert, A.; Möser, C.V.; Niederberger, E. The Specific IKKε/TBK1 Inhibitor Amlexanox Suppresses Human Melanoma by the Inhibition of Autophagy, NF-κB and MAP Kinase Pathways. Int. J. Mol. Sci. 2020, 21, 4721. https://doi.org/10.3390/ijms21134721

AMA Style

Möller M, Wasel J, Schmetzer J, Weiß U, Meissner M, Schiffmann S, Weigert A, Möser CV, Niederberger E. The Specific IKKε/TBK1 Inhibitor Amlexanox Suppresses Human Melanoma by the Inhibition of Autophagy, NF-κB and MAP Kinase Pathways. International Journal of Molecular Sciences. 2020; 21(13):4721. https://doi.org/10.3390/ijms21134721

Chicago/Turabian Style

Möller, Moritz, Julia Wasel, Julia Schmetzer, Ulrike Weiß, Markus Meissner, Susanne Schiffmann, Andreas Weigert, Christine V. Möser, and Ellen Niederberger. 2020. "The Specific IKKε/TBK1 Inhibitor Amlexanox Suppresses Human Melanoma by the Inhibition of Autophagy, NF-κB and MAP Kinase Pathways" International Journal of Molecular Sciences 21, no. 13: 4721. https://doi.org/10.3390/ijms21134721

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