Journal Article

Targeting GSK3 and Associated Signaling Pathways Involved in Cancer

Duda, Przemysław, Akula, Shaw M., Abrams, Stephen L., Gizak, Agnieszka, Cervello, Melchiorre, Martelli, Alberto M., Cocco, Lucio, McCubrey, James A., Libra, Massimo, Montalto, Giuseppe, Rakus, Dariusz, Steelman, Linda S., Ratti, Stefano, Candido, Saverio

2020

Overview

Glycogen synthase kinase 3 (GSK-3) is a serine/threonine (S/T) protein kinase. Although GSK-3 originally was identified to have functions in regulation of glycogen synthase, it was subsequently determined to have roles in multiple normal biochemical processes as well as various disease conditions. GSK-3 is sometimes referred to as a moonlighting protein due to the multiple substrates and processes which it controls. Frequently, when GSK-3 phosphorylates proteins, they are targeted for degradation. GSK-3 is often considered a component of the PI3K/PTEN/AKT/GSK-3/mTORC1 pathway as GSK-3 is frequently phosphorylated by AKT which regulates its inactivation. AKT is often active in human cancer and hence, GSK-3 is often inactivated. Moreover, GSK-3 also interacts with WNT/β-catenin signaling and β-catenin and other proteins in this pathway are targets of GSK-3. GSK-3 can modify NF-κB activity which is often expressed at high levels in cancer cells. Multiple pharmaceutical companies developed small molecule inhibitors to suppress GSK-3 activity. In addition, various natural products will modify GSK-3 activity. This review will focus on the effects of small molecule inhibitors and natural products on GSK-3 activity and provide examples where these compounds were effective in suppressing cancer growth.

• Publisher: MDPI,MDPI AG
• Subject: drug resistance / Glycogen Synthase Kinase 3 - metabolism / Glycogen Synthase Kinase 3 - physiology / GSK-3 / Humans / natural products / Neoplasms - metabolism / Phosphorylation / Protein-Serine-Threonine Kinases - metabolism / Proto-Oncogene Proteins c-akt - metabolism / Review / targeted therapy / Wnt Signaling Pathway - physiology