Journal Article

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

Martelli, Alberto M., Paganelli, Francesca, Chiarini, Francesca, McCubrey, James A., Evangelisti, Camilla

2022

Overview

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.

• Publisher: MDPI AG,MDPI
• Subject: Alzheimer's disease / Apoptosis / Blood diseases / c-Myc protein / Cancer / Cancer therapies / Cell cycle / chronic hematological malignancies / Chronic lymphocytic leukemia / chronic myelogenous leukemia / Chronic myeloid leukemia / Development and progression / Enzymes / Glucose metabolism / Glycogen / Glycogen synthase kinase 3 / Growth factors / GSK-3 / Hematology / Isoforms / Kinases / Leukemia / Lymphocytes B / Medical research / Medicine, Experimental / Metabolism / Multiple myeloma / Mutation / Myc protein / Myeloid leukemia / Non-Hodgkin's lymphoma / Oncology, Experimental / paralogs / Phosphatase / Phosphorylation / Protein kinase / Protein kinases / Protein-serine/threonine kinase / Proteins / Regulation / Review / Risk factors / Skin cancer / Synthesis / targeted therapy / Tumor suppressor genes / Tumors / β-Catenin