Nature：癌症治疗新靶位

　　

生物通报道，来自斯坦福大学医学院病理学（Department of Pathology, Stanford University School of Medicine）The Cleary Lab的Michael L. Cleary教授带领的研究小组近期研究表明，以糖原合成酶激酶-3为靶位，对白血病治疗具有重要作用。Michael L. Cleary教授的实验室主要研究癌症的分子病理机制。目前为止，Cleary实验室已经鉴定了诱发白血病的几个基因，近期正研究这些基因的功能。

 

糖原合成酶激酶-3 (glycogen synthase kinase-3, GSK-3)是一个多功能的丝氨酸/苏氨酸蛋白激酶,不仅参与肝糖代谢过程,而且还参与Wnt和Hedgehog信号通路,通过磷酸化多种底物蛋白来调节细胞的生理过程。因此，GSK-3是目前多种疾病的最佳治疗靶位。然而，到现在为止，还有充足的证据证实GSK-3是治疗恶性肿瘤的最适靶位。

 

Michael L. Cleary教授从病理、药理和遗传学角度阐述GSK-3是MLL白血病的适宜治疗靶位，通常MLL白血病患者GSK-3基因发生突变，GSK-3突变的患者往往预后不良。先前的研究认为，GSK-3能抑制瘤形成的信号通路，但是现在研究发现，GSK-3可促进MLL白血病患者癌细胞增殖，促进癌细胞转化，最终使周期依赖性蛋白激酶抑制子P27^Kip1失去稳定性。

 

Cleary教授的研究小组在MLL白血病小鼠模型中抑制GSK3的活性，结果发现，GSK-3是治疗MLL白血病的适宜靶位。

 

GSK-3抑制剂作为目前备受关注的小分子抑制剂,对治疗神经退化性疾病、癌症、Ⅱ型糖尿病具有潜在的疗效。

 

原文摘要：Glycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapy

 

Michael L. Cleary教授实验室主页

http://www.stanford.edu/group/cleary/

 

【Abstract】

Glycogen synthase kinase 3 (GSK3) is a multifunctional serine/threonine kinase that participates in numerous signalling pathways involved in diverse physiological processes. Several of these pathways are implicated in disease pathogenesis, which has prompted efforts to develop GSK3-specific inhibitors for therapeutic applications. However, before now, there has been no strong rationale for targeting GSK3 in malignancies. Here we report pharmacological, physiological and genetic studies that demonstrate an oncogenic requirement for GSK3 in the maintenance of a specific subtype of poor prognosis human leukaemia, genetically defined by mutations of the MLL proto-oncogene. In contrast to its previously characterized roles in suppression of neoplasia-associated signalling pathways, GSK3 paradoxically supports MLL leukaemia cell proliferation and transformation by a mechanism that ultimately involves destabilization of the cyclin-dependent kinase inhibitor p27Kip1. Inhibition of GSK3 in a preclinical murine model of MLL leukaemia provides promising evidence of efficacy and earmarks GSK3 as a candidate cancer drug target.

 

（生物通 张欢）