GSK-3 Promotes Cell Survival, Growth, and PAX3 Levels in Human Melanoma Cells

GSK-3 is a serine/threonine kinase involved in a diverse range of cellular processes. GSK-3 exists in two isoforms, GSK-3 alpha and GSK-3 beta, which possess some functional redundancy but also play distinct roles depending on developmental and cellular context. In this article, we found that GSK-3 actively promoted cell growth and survival in melanoma cells, and blocking this activity with small-molecule inhibitor SB216763 or gene-specific siRNA decreased proliferation, increased apoptosis, and altered cellular morphology. These alterations coincided with loss of PAX3, a transcription factor implicated in proliferation, survival, and migration of developing melanoblasts. We further found that PAX3 directly interacted with and was phosphorylated in vitro on a number of residues by GSK-3 beta. In melanoma cells, direct inhibition of PAX3 lead to cellular changes that paralleled the response to GSK-3 inhibition. Maintenance of PAX3 expression protected melanoma cells from the anti-tumor effects of SB216763. These data support a model wherein GSK-3 regulates proliferation and morphology of melanoma through phosphorylation and increased levels of PAX3. Mol Cancer Res; 10(8); 1065-76. (C) 2012 AACR.