Nuclear Factor-kappa B (NF-kappa B) is an inducible transcription factor that regulates the expression of many genes involved in the immune response. Recently, NF-kappa B activity has been shown to be upregulated in many cancers, including melanoma. Data indicate that the enhanced activation of NF-kappa B may be due to deregulations in upstream signaling pathways such as Ras/Raf, PI3K/Akt, and NIK. Multiple studies have shown that NF-kappa B is involved in the regulation of apoptosis, angiogenesis, and tumor cell invasion, all of which indicate the important role of NF-kappa B in tumorigenesis. Thus, understanding the molecular mechanism of melanoma progression will aid in designing new therapeutic approaches for melanoma. In this review, the association between NF-kappa B and melanoma tumorigenesis are discussed. Additionally, the potential of emerging selective NF-kappa B inhibitors for the treatment of melanoma is reviewed.

Purpose: Constitutive activation of inhibitor of nB kinase (IKK) confers melanoma resistance to apoptosis and chemotherapy.Whether IKK is able to serve as a therapeutic target in melanoma is unknown. We explored the possibility of exploiting IKK as a therapeutic target in melanoma by using BMS-345541, a novel compound with a highly selective IKKh inhibitory activity, to trigger melanoma cell apoptosis. Experimental Design:Three human melanoma cell lines (SK-MEL-5, Hs 294T, and A375), all of which have high constitutive IKK activities, served as in vitro and in vivo melanoma models for treatment with BMS-345541. Two known antitumor drugs (temozolomide and bortezomib) were used as parallel controls for evaluation of the therapeutic efficiency and toxicity of BMS-345541. The effects of BMS-345541on nuclear factor nB (NF-nB) signaling and on the apoptosis machinery were investigated. Results: Inhibition of constitutive IKK activity by BMS-345541resulted in the reduction of NF-nB activity, CXCL1 chemokine secretion by cultured melanoma cells and melanoma cell survival in vitro and in vivo. The effect of BMS-345541on tumor cell growth was through mitochondriamediated apoptosis, based on the release of apoptosis-inducing factor, dissipation of mitochondrial membrane potential, and reduced ratio of B cell lymphoma gene-2 (Bcl-2)/Bcl-associated X protein (Bax) in mitochondria. The BMS-345541execution of apoptosis was apoptosis-inducing factor^dependent, but largely caspase-independent. Conclusion: BMS-345541 down-regulation of IKK activity results in mitochondria-mediated apoptosis of tumor cells because the programmed cell death machinery in melanoma cells is highly regulated by NF-nB signaling.Therefore, IKK may serve as a potential target for melanoma therapy.

Oncogene-induced senescence can provide a protective mechanism against tumour progression. However, production of cytokines and growth factors by senescent cells may contribute to tumour development. Thus, it is unclear whether induction of senescence represents a viable therapeutic approach. Here, using a mouse model with orthotopic implantation of metastatic melanoma tumours taken from 19 patients, we observed that targeting aurora kinases with MLN8054/MLN8237 impaired mitosis, induced senescence and markedly blocked proliferation in patient tumour implants. Importantly, when a subset of tumour-bearing mice were monitored for tumour progression after pausing MLN8054 treatment, 50% of the tumours did not progress over a 12-month period. Mechanistic analyses revealed that inhibition of aurora kinases induced polyploidy and the ATM/Chk2 DNA damage response, which mediated senescence and a NF-κB-related, senescence-associated secretory phenotype (SASP). Blockade of IKKβ/NF-κB led to reversal of MLN8237-induced senescence and SASP. Results demonstrate that removal of senescent tumour cells by infiltrating myeloid cells is crucial for inhibition of tumour re-growth. Altogether, these data demonstrate that induction of senescence, coupled with immune surveillance, can limit melanoma growth.