Mol Cancer Res：GSK-3或成黑色素瘤治疗新靶点

糖原合成酶激酶-3（glycogen synthase kinase-3，GSK-3）是一种多功能的丝氨酸/苏氨酸蛋白激酶，是细胞内多种信号转导通路中的重要成分，不仅参与细胞内糖代谢过程而且还参与细胞增殖、细胞分化和细胞凋亡等多种重要生理过程。

GSK-3活性受多种机制调节，其活性调节异常时可引起多种重大疾病如糖尿病、神经退行性疾病和肿瘤等。GSK-3已成为许多疾病治疗靶点，目前针对GSK-3靶点开发的抑制剂主要是ATP竞争性的小分子GSK-3抑制剂。

GSK-3存在两种异构体，GSK-3α和GSK-3β，这两种亚型具有一些相似的功能，但也发挥不同的角色，这取决于细胞发展状态。近日，Molecular Cancer Research杂志上刊登的一则研究中，研究人员发现GSK-3能促进黑色素瘤细胞的生长和生存，用小分子抑制剂SB216763或基因特异性siRNA降低GSK-3表达后，黑色素瘤细胞的增殖降低，细胞凋亡增加，同时细胞形态也发生改变。

上述这些变化与黑色素瘤细胞PAX3的缺失呈正相关性，PAX3是一种转录因子，在黑素细胞的增殖、存活和迁移中发挥作用。进一步体外研究发现，PAX3能与GSK-3β残基直接互动，并被磷酸化。在黑色素瘤细胞中，直接抑制PAX3导致类似的黑色素瘤细胞增殖凋亡上的变化，这种变化与抑制GSK-3所带来的效应是类似的。维持住PAX3的表达能保护黑色素细胞免受SB216763的抗肿瘤作用。

这些数据证实GSK-3通过调控PAX3的磷酸化，提高PAX3表达水平影响黑色素瘤细胞的增殖和形态。

doi:10.1158/1541-7786.MCR-11-0387
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Glycogen Synthase Kinase-3 promotes cell survival, growth and PAX3 levels in human melanoma cells

Jennifer D Kubic, Joseph B Mascarenhas, Takumi Iizuka, Don Wolfgeher, and Deborah Lang*

Glycogen Synthase Kinase-3 (GSK-3) is a serine/threonine kinase involved in a diverse range of cellular processes. GSK-3 exists in two isoforms, GSK-3α and GSK-3β, which possess some functional redundancy but also play distinct roles depending on developmental and cellular context. In this report 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-3β. 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.