Pathobiology and Therapeutic Relevance of GSK-3 in Chronic Hematological Malignancies

Cells

Francesca Chiarini¹  Alberto M. Martelli²  Camilla Evangelisti²  Francesca Paganelli²  James A. McCubrey³ 

[1] CNR-Institute of Molecular Genetics “Luigi Luca Cavalli-Sforza”, Unit of Bologna, 40136 Bologna, Italy;Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy;Department of Microbiology and Immunology, East Carolina University, Greenville, NC 27834, USA;

关键词: GSK-3;    paralogs;    chronic hematological malignancies;    targeted therapy;    chronic myelogenous leukemia;    chronic lymphocytic leukemia;   

DOI  :  10.3390/cells11111812

来源: DOAJ

【 摘 要 】

Glycogen synthase kinase-3 (GSK-3) is an evolutionarily conserved, ubiquitously expressed, multifunctional serine/threonine protein kinase involved in the regulation of a variety of physiological processes. GSK-3 comprises two isoforms (α and β) which were originally discovered in 1980 as enzymes involved in glucose metabolism via inhibitory phosphorylation of glycogen synthase. Differently from other proteins kinases, GSK-3 isoforms are constitutively active in resting cells, and their modulation mainly involves inhibition through upstream regulatory networks. In the early 1990s, GSK-3 isoforms were implicated as key players in cancer cell pathobiology. Active GSK-3 facilitates the destruction of multiple oncogenic proteins which include β-catenin and Master regulator of cell cycle entry and proliferative metabolism (c-Myc). Therefore, GSK-3 was initially considered to be a tumor suppressor. Consistently, GSK-3 is often inactivated in cancer cells through dysregulated upstream signaling pathways. However, over the past 10–15 years, a growing number of studies highlighted that in some cancer settings GSK-3 isoforms inhibit tumor suppressing pathways and therefore act as tumor promoters. In this article, we will discuss the multiple and often enigmatic roles played by GSK-3 isoforms in some chronic hematological malignancies (chronic myelogenous leukemia, chronic lymphocytic leukemia, multiple myeloma, and B-cell non-Hodgkin’s lymphomas) which are among the most common blood cancer cell types. We will also summarize possible novel strategies targeting GSK-3 for innovative therapies of these disorders.

【 授权许可】

Unknown