GSK-3 as potential target for therapeutic intervention in cancer

// James A. McCubrey 1 , Linda S. Steelman 1 , Fred E. Bertrand 2 , Nicole M. Davis 1 , Melissa Sokolosky 1 , Steve L. Abrams 1 , Giuseppe Montalto 3 , Antonino B. D’Assoro 4 , Massimo Libra 5 , Ferdinando Nicoletti 5 , Roberta Maestro 6 , Jorg Basecke 7,8 , Dariusz Rakus 9 , Agnieszka Gizak 9 Zoya Demidenko 10 , Lucio Cocco 11 , Alberto M. Martelli 11 and Melchiorre Cervello 12 1 Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University Greenville, NC, USA 2 Department of Oncology, Brody School of Medicine at East Carolina University Greenville, NC, USA 3 Biomedical Department of Internal Medicine and Specialties, University of Palermo, Palermo, Italy 4 Department of Medical Oncology, Mayo Clinic Cancer Center, Rochester, MN, USA 5 Department of Bio-Medical Sciences, University of Catania, Catania, Italy 6 Experimental Oncology 1, CRO IRCCS, National Cancer Institute, Aviano, Pordenone, Italy. 7 Department of Medicine, University of Göttingen, Göttingen, Germany 8 Sanct-Josef-Hospital Cloppenburg, Department of Hematology and Oncology, Cloppenburg, Germany 9 Department of Animal Molecular Physiology, Institute of Experimental Biology, Wroclaw University, Wroclaw, Poland 10 Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA 11 Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy 12 Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare “Alberto Monroy”, Palermo, Italy Correspondence: James A. McCubrey, email: // Keywords : GSK-3, cancer stem cells, Wnt/beta-catenin, PI3K, Akt, mTOR(definition), Hedgehog, Notch, Targeted Therapy, Therapy Resistance, Mutations, Rapamycin(definition) Received : April 24, 2014 Accepted : May 28, 2014 Published : May 28, 2014 Abstract The serine/threonine kinase glycogen synthase kinase-3 (GSK-3) was initially identified and studied in the regulation of glycogen synthesis. GSK-3 functions in a wide range of cellular processes. Aberrant activity of GSK-3 has been implicated in many human pathologies including: bipolar depression, Alzheimer’s disease, Parkinson’s disease, cancer, non-insulin-dependent diabetes mellitus (NIDDM) and others. In some cases, suppression of GSK-3 activity by phosphorylation by Akt and other kinases has been associated with cancer progression. In these cases, GSK-3 has tumor suppressor functions. In other cases, GSK-3 has been associated with tumor progression by stabilizing components of the beta-catenin complex. In these situations, GSK-3 has oncogenic properties. While many inhibitors to GSK-3 have been developed, their use remains controversial because of the ambiguous role of GSK-3 in cancer development. In this review, we will focus on the diverse roles that GSK-3 plays in various human cancers, in particular in solid tumors. Recently, GSK-3 has also been implicated in the generation of cancer stem cells in various cell types. We will also discuss how this pivotal kinase interacts with multiple signaling pathways such as: PI3K/PTEN/Akt/mTORC1, Ras/Raf/MEK/ERK, Wnt/beta-catenin, Hedgehog, Notch and others.