The IKK alpha-dependent non-canonical pathway of NF-kappa B activation is constitutively active and modulates progression-related functions in a subset of human melanomas

Abstract

Owing to activation of several resistance-mediating pathways including NF-kappa B signaling, metastasized melanoma is almost universally resistant against chemotherapy. Given that blocking of NF-kappa B either by proteasome-, pan-IKK- or selective IKK beta-inhibitors may increase the susceptibility of melanoma cells to chemotherapy, we have assessed the role of the second kinase within the IKK complex, IKK alpha. While expression of IKK alpha and overall activation of NF-kappa B were heterogeneous, the IKK alpha-specific p100/p52 processing was detected in a small subset of melanomas (1/9 primary and 1/12 metastatic melanomas) as well as in 1/8 melanoma cell lines. Down-modulation of IKK alpha by siRNA resulted in diminution of doxorubicin-induced NF-kappa B activation, constitutive and TNF alpha-stimulated expression of CXCL8 and ICAM-1, and cell migration. In contrast, overexpression of IKK alpha in melanoma cells did not significantly affect progression-related functions. Thus, IKK alpha may be a worthwhile target only in selected individualized therapies but not in general melanoma therapy.