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Constitutive Activation of Akt/Protein Kinase B in Melanoma Leads to Up-Regulation of Nuclear Factor-B and Tumor Progression¹

Departments of Veterans Affairs [A. R.], Cancer Biology [P. D., A. R.], Nephrology [A. B. S.], and Medicine, Division of Dermatology [D. L. E.], Vanderbilt University School of Medicine, Nashville, Tennessee 37232

The serine/threonine kinase Akt/protein kinase B and the pleiotropic transcription factor nuclear factor-B [NF-B (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-B 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-B 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-B promoter activity. These results indicate that activation of Akt kinase is linked to enhanced NF-B nuclear localization and transactivation. We propose that activation of Akt may be an early marker for tumor progression in melanoma.

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