Functional and therapeutic significance of Akt deregulation in malignant melanoma

Abstract

Identification of specific genes or signaling pathways involved in development of melanoma could lead to new therapies that target and correct these defects. Recent studies have revealed deregulation of the Akt signaling pathway occuring in 43–67% of melanomas. Akt kinase family members, Akt1/PKBα, Akt2/PKBβ and Akt3/PKBγ, share extensive structural similarity and perform common as well as unique functions within cells. The Akt signaling cascade initiates at the cell surface when growth factors or other extracellular stimuli activate phosphoinositide 3-kinase (PI3K). Activated PI3K generates a lipid second messenger, phosphatidylinositol-3,4,5-trisphosphate (PIP₃), causing translocation of Akt to the plasma membrane where it becomes phosphorylated and activated. The balance of cellular PIP₃ is regulated primarily by a phosphatase called PTEN that reduces PIP₃ levels thereby lowering Akt activity. In melanomas, decreased PTEN activity elevates PIP₃ levels resulting in Akt activation. Active Akt then phosphorylates downstream cellular proteins that promote melanoma cell proliferation and survival. Recently, Akt3 was discovered to be the predominant isoform activated in sporadic melanomas. Levels of activity increased during melanoma progression with metastatic melanomas having the highest activity. Although mechanisms of Akt3 activation remain to be fully characterized, overexpression of Akt3 and decreased PTEN activity play important roles in this process. Targeted reduction of Akt3 activity decreased survival of melanoma tumor cells leading to inhibition of tumor development, which may be therapeutically effective for shrinking tumors in melanoma patients. This review surveys recent developments in Akt deregulation in melanoma and its potential as a selective therapeutic target in patients in the advanced stages of this disease.