Roles of GSK-3 and microRNAs on epithelial mesenchymal transition and cancer stem cells.

James A Mccubrey,Agnieszka Gizak,Joanna Dulińska-Litewka,Massimo Libra,Saverio Candido,Luca M Neri,Lucio Cocco,Dariusz Rakus,Stephen L Abrams,Linda S Steelman,Ferdinando Nicoletti,Li V Yang,Piotr Laidler,Luca Falzone,Kvin Lertpiriyapong,Melchiorre Cervello,Alberto M Martelli,Timothy L Fitzgerald,Giuseppe Montalto

doi:10.18632/oncotarget.13991

Abstract

Various signaling pathways exert critical roles in the epithelial to mesenchymal transition (EMT) and cancer stem cells (CSCs). The Wnt/beta-catenin, PI3K/PTEN/Akt/mTORC, Ras/Raf/MEK/ERK, hedgehog (Hh), Notch and TP53 pathways elicit essential regulatory influences on cancer initiation, EMT and progression. A common kinase involved in all these pathways is moon-lighting kinase glycogen synthase kinase-3 (GSK-3). These pathways are also regulated by micro-RNAs (miRs). TP53 and components of these pathways can regulate the expression of miRs. Targeting members of these pathways may improve cancer therapy in those malignancies that display their abnormal regulation. This review will discuss the interactions of the multi-functional GSK-3 enzyme in the Wnt/beta-catenin, PI3K/PTEN/Akt/mTORC, Ras/Raf/MEK/ERK, Hh, Notch and TP53 pathways. The regulation of these pathways by miRs and their effects on CSC generation, EMT, invasion and metastasis will be discussed.

Highlights

Glycogen synthase kinase-3 (GSK-3) is moonlighting kinase which phosphorylates multiple proteins on serine (S) and threonine (T) residues
A pathway consisting of miR-451, c-Myc, ERK, GSK-3beta and Snail has been shown to be important in the docetaxel-resistance of lung adenocarcinoma cell models (LAD) which have some phenotypes associated www.impactjournals.com/oncotarget with cells having undergone epithelial to mesenchymal transition (EMT) and have increased invasive and migratory properties. c-Myc was shown to be a target of miR-451
GSK-3 activity can be dysregulated by various signal transduction pathways that are themselves aberrantly regulated in cancer often due to genetic and epigenetic www.impactjournals.com/oncotarget mechanisms

Summary

Introduction

Glycogen synthase kinase-3 (GSK-3) is moonlighting kinase which phosphorylates multiple proteins on serine (S) and threonine (T) residues. Mutations which result in abnormal GSK-3 activity can have effects on the Wnt/beta-catenin pathway and alter the regulation of EMT, and cancer development and metastasis. The Wnt/beta-catenin and PI3K/PTEN/Akt/mTORC1 signaling pathways will suppress GSK-3 activity.

Results

Conclusion