Deregulated expression or activity of
kinases can lead to
melanomas, but often the particular
kinase isoform causing the effect is not well established, making identification and validation of different
isoforms regulating disease development especially important. To accomplish this objective, an
siRNA screen was undertaken that which identified
glycogen synthase kinase 3α (GSK3α) as an important
melanoma growth regulator. Melanocytes and
melanoma cell lines representing various stages of
melanoma tumor progression expressed both GSK3α and GSK3β, but analysis of
tumors in patients with
melanoma showed elevated expression of GSK3α in 72% of samples, which was not observed for GSK3β. Furthermore, 80% of
tumors in patients with
melanoma expressed elevated levels of catalytically active phosphorylated GSK3α (pGSK3αY279), but not phosphorylated GSK3β (pGSK3βY216).
siRNA-mediated reduction in GSK3α
protein levels reduced
melanoma cell survival and proliferation, sensitized cells to apoptosis-inducing agents and decreased xenografted
tumor development by up to 56%. Mechanistically, inhibiting GSK3α expression using
siRNA or the pharmacological agent
AR-A014418 arrested
melanoma cells in the G0/G1 phase of the cell cycle and induced apoptotic death to retard
tumorigenesis. Therefore, GSK3α is a key therapeutic target in
melanoma.