Ruvolo Peter P
Department of Leukemia, Unit 448, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, United States.
Adv Biol Regul. 2017 Aug;65:26-35. doi: 10.1016/j.jbior.2017.05.001. Epub 2017 May 8.
While leukemias represent a diverse set of diseases with malignant cells derived from myeloid or lymphoid origin, a common feature is the dysregulation of signal transduction pathways that influence leukemogeneisis, promote drug resistance, and favor leukemia stem cells. Mutations in PI3K, PTEN, RAS, or other upstream regulators can activate the AKT kinase which has central roles in supporting cell proliferation and survival. A major target of AKT is Glycogen Synthase Kinase 3 (GSK3). GSK3 has two isoforms (alpha and beta) that were studied as regulators of metabolism but emerged as central players in cancer in the early 1990s. GSK3 is unique in that the isoforms are constitutively active. Active GSK3 promotes destruction of oncogenic proteins such as beta Catenin, c-MYC, and MCL-1 and thus has tumor suppressor properties. In AML, inactivation of GSK3 is associated with poor overall survival. Interestingly in some leukemias GSK3 targets a tumor suppressor and thus the kinases can act as tumor promoters in those instances. An example is GSK3 targeting p27Kip1 in AML with MLL translocation. This review will cover the role of GSK3 in various leukemias both as tumor suppressor and tumor promoter. We will also briefly cover current state of GSK3 inhibitors for leukemia therapy.
白血病是一组多样的疾病，其恶性细胞起源于髓系或淋巴系，一个共同特征是影响白血病发生、促进耐药性并有利于白血病干细胞的信号转导通路失调。PI3K、PTEN、RAS或其他上游调节因子的突变可激活AKT激酶，该激酶在支持细胞增殖和存活中起核心作用。AKT的一个主要靶点是糖原合酶激酶3（GSK3）。GSK3有两种亚型（α和β），最初作为代谢调节因子进行研究，但在20世纪90年代初成为癌症中的关键角色。GSK3的独特之处在于其亚型是组成型激活的。活性GSK3促进致癌蛋白如β-连环蛋白、c-MYC和MCL-1的降解，因此具有肿瘤抑制特性。在急性髓系白血病（AML）中，GSK3失活与总体生存率低相关。有趣的是，在某些白血病中，GSK3靶向一种肿瘤抑制因子，因此在这些情况下该激酶可作为肿瘤促进因子。一个例子是在伴有MLL易位的AML中，GSK3靶向p27Kip1。本综述将涵盖GSK3在各种白血病中作为肿瘤抑制因子和肿瘤促进因子的作用。我们还将简要介绍用于白血病治疗的GSK3抑制剂的现状。
