title: The protein kinase IKKepsilon contributes to tumour growth and tumour pain in a melanoma model.
abstract: Inhibitor-kappaB kinase epsilon (IKKε) constitutes a non-canonical I-κB kinase, which amongst others modulates NF-κB activity. IKKε and NF-κB have both been described for their role in cell proliferation and their dysregulation has been associated with tumourigenesis and metastasis in multiple cancer types. Accordingly, overexpression and constitutive activation of NF-κB have also been shown in melanoma, however, the role of IKKε in this cancer type has not been investigated so far. Thus, we determined IKKε expression in malignant melanoma cells and we were able to show a significant overexpression of IKKε in tumour cells in comparison to melanocytes. Inhibition of IKKε either by shRNA or the pharmacological inhibitor amlexanox resulted in reduced cell proliferation associated with a cell cycle block in the G1-phase. Functional analysis indicated that NF-κB, Akt1 and MAPK pathways might be involved in the IKKε-mediated effects. In vivo, we applied a mouse melanoma skin cancer model to assess tumour growth and melanoma-associated pain in IKKε knockout mice as well as C57BL/6 mice after inoculation with IKKε-negative cells. In IKKε knockout mice, tumour growth was not altered as compared to IKKε wild type mice. However, melanoma associated pain was strongly suppressed accompanied by a reduced mRNA expression of a number of pain-relevant genes. In contrast, after inoculation of IKKε-depleted tumour cells, the development of melanoma was almost completely prevented. In conclusion, our data suggest that IKKε in the tumour plays an essential role in tumour initiation and progression while IKKε expression in tumour surrounding tissues contributes to melanoma-associated pain.
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany. Electronic address: ch.moeser@em.uni-frankfurt.de.
authors.forename: Christine V
authors.initials: CV
authors.lastname: Möser
authors.affiliation: Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Meissner
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Laarmann
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Olbrich
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Tanya S
authors.initials: TS
authors.lastname: King-Himmelreich
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Miriam C
authors.initials: MC
authors.lastname: Wolters
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany; Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Project Group for Translational Medicine & Pharmacology (TMP), 60596 Frankfurt/Main, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Ellen
authors.initials: E
authors.lastname: Niederberger
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D002453:Cell Cycle; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008544:Melanocytes / Q000201:enzymology; D008545:Melanoma / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D008546:Melanoma, Experimental / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010146:Pain / Q000503:physiopathology*; D012878:Skin Neoplasms / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology
chemical_list: D000631:Aminopyridines; C045742:amlexanox; D051550:I-kappa B Kinase
keywords: Amlexanox; IKKε; Melanoma; NF-κB; Pain; Tumour growth