Constitutive activation of Akt/protein kinase B in melanoma leads to up-regulation of nuclear factor-κB and tumor progression

The serine/threonine kinase Akt/protein kinase B and the pleiotropic transcription factor nuclear factor-κB [NF-κB (p50/p65) play important roles in the control of cell proliferation, apoptosis, and oncogenesis. Previous studies from our laboratory have shown the constitutive activation of NF-κB in melanoma cells. However, the mechanism of this activation is not clearly understood. The purpose of this study was to explore the role of Akt in the activation of NF-κB during melanoma tumor progression. Based on our observation that two of the five melanoma cell lines examined exhibit constitutive Akt activation, we evaluated Akt activation by immunohistochemistry in a series of pigmented skin lesions using an antibody specific for phospho-Akt Ser-473. Normal and slightly dysplastic nevi exhibited no significant Akt expression, in marked contrast to the dramatic Akt immunoreactivity seen in severely dysplastic nevi and melanomas (66.3% positive). When these same lesions were stained for nuclear p65, a similar expression pattern was observed. In addition, interruption of Akt activation resulted in increased apoptosis and decreased NF-κB promoter activity. These results indicate that activation of Akt kinase is linked to enhanced NF-κB nuclear localization and transactivation. We propose that activation of Akt may be an early marker for tumor progression in melanoma.