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The protein kinase IKKepsilon contributes to tumour growth and tumour pain in a melanoma model

: Möser, C.V.; Meissner, M.; Laarmann, K.; Olbrich, K.; King-Himmelreich, T.S.; Wolters, M.C.; Geisslinger, G.; Niederberger, E.


Biochemical pharmacology 103 (2016), pp.64-73
ISSN: 0006-2952
ISSN: 1873-2968
Journal Article
Fraunhofer IME ()

Inhibitor-kappaB kinase epsilon (IKK epsilon) constitutes a non-canonical I-kappa B kinase, which amongst others modulates NF-kappa B activity. IKK epsilon and NF-kappa B 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-kappa B have also been shown in melanoma, however, the role of IKK epsilon in this cancer type has not been investigated so far. Thus, we determined IKK epsilon expression in malignant melanoma cells and we were able to show a significant overexpression of IKKe in tumour cells in comparison to melanocytes. Inhibition of IKK epsilon 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-kappa B, Akt1 and MAPK pathways might be involved in the IKK epsilon-mediated effects. In vivo, we applied a mouse melanoma skin cancer model to assess tumour growth and melanoma-associated pain in IKK epsilon knockout mice as well as C57BL/6 mice after inoculation with IKK epsilon-negative cells. In Has knockout mice, tumour growth was not altered as compared to IKK epsilon 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 IKK epsilon-depleted tumour cells, the development of melanoma was almost completely prevented. In conclusion, our data suggest that Has in the tumour plays an essential role in tumour initiation and progression while IKK epsilon expression in tumour surrounding tissues contributes to melanoma-associated pain.