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 t...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-07-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/13/4721 |
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| author | Moritz Möller Julia Wasel Julia Schmetzer Ulrike Weiß Markus Meissner Susanne Schiffmann Andreas Weigert Christine V. Möser Ellen Niederberger |
| author_facet | Moritz Möller Julia Wasel Julia Schmetzer Ulrike Weiß Markus Meissner Susanne Schiffmann Andreas Weigert Christine V. Möser Ellen Niederberger |
| author_sort | Moritz Möller |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T18:44:06Z |
| format | Article |
| id | doaj.art-f7f72b0fe6d848038ff06eac1ceccf61 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T18:44:06Z |
| publishDate | 2020-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-f7f72b0fe6d848038ff06eac1ceccf612023-11-20T05:38:35ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-07-012113472110.3390/ijms21134721The Specific IKKε/TBK1 Inhibitor Amlexanox Suppresses Human Melanoma by the Inhibition of Autophagy, NF-κB and MAP Kinase PathwaysMoritz Möller0Julia Wasel1Julia Schmetzer2Ulrike Weiß3Markus Meissner4Susanne Schiffmann5Andreas Weigert6Christine V. Möser7Ellen Niederberger8Pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Faculty of Medicine, Goethe-University Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, GermanyPharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Faculty of Medicine, Goethe-University Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, GermanyPharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Faculty of Medicine, Goethe-University Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, GermanyPharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Faculty of Medicine, Goethe-University Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, GermanyDepartment of Dermatology, Venereology and Allergology, Faculty of Medicine, Goethe-University Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt, GermanyFraunhofer Institute for Molecular Biology and Applied Ecology (IME), Branch for Translational Medicine and Pharmacology TMP, Theodor Stern-Kai 7, 60590 Frankfurt am Main, GermanyInstitute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, GermanyPharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Faculty of Medicine, Goethe-University Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, GermanyPharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Faculty of Medicine, Goethe-University Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, GermanyInhibitor-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.https://www.mdpi.com/1422-0067/21/13/4721melanomaIKKεTBK1amlexanoxtumor growthNF-кB |
| spellingShingle | Moritz Möller Julia Wasel Julia Schmetzer Ulrike Weiß Markus Meissner Susanne Schiffmann Andreas Weigert Christine V. Möser Ellen Niederberger 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 melanoma IKKε TBK1 amlexanox tumor growth NF-кB |
| title | The Specific IKKε/TBK1 Inhibitor Amlexanox Suppresses Human Melanoma by the Inhibition of Autophagy, NF-κB and MAP Kinase Pathways |
| title_full | The Specific IKKε/TBK1 Inhibitor Amlexanox Suppresses Human Melanoma by the Inhibition of Autophagy, NF-κB and MAP Kinase Pathways |
| title_fullStr | The Specific IKKε/TBK1 Inhibitor Amlexanox Suppresses Human Melanoma by the Inhibition of Autophagy, NF-κB and MAP Kinase Pathways |
| title_full_unstemmed | The Specific IKKε/TBK1 Inhibitor Amlexanox Suppresses Human Melanoma by the Inhibition of Autophagy, NF-κB and MAP Kinase Pathways |
| title_short | The Specific IKKε/TBK1 Inhibitor Amlexanox Suppresses Human Melanoma by the Inhibition of Autophagy, NF-κB and MAP Kinase Pathways |
| title_sort | specific ikkε tbk1 inhibitor amlexanox suppresses human melanoma by the inhibition of autophagy nf κb and map kinase pathways |
| topic | melanoma IKKε TBK1 amlexanox tumor growth NF-кB |
| url | https://www.mdpi.com/1422-0067/21/13/4721 |
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