Abstract
The serine/threonine kinase glycogen synthase kinase-3 (GSK-3) was initially identified because of its key role in the regulation of glycogen synthesis. However, it is now well-established that GSK-3 performs critical functions in many cellular processes, such as apoptosis, tumor growth, cell invasion, and metastasis. Aberrant GSK-3 activity has been associated with many human diseases, including cancer, highlighting its potential therapeutic relevance as a target for anticancer therapy. Recently, newly emerging data have demonstrated the pivotal role of GSK-3 in the anticancer immune response. In the last few years, many GSK-3 inhibitors have been developed, and some are currently being tested in clinical trials. This review will discuss preclinical and initial clinical results with GSK-3β inhibitors, highlighting the potential importance of this target in cancer immunotherapy. As described in this review, GSK-3 inhibitors have been shown to have antitumor activity in a wide range of human cancer cells, and they may also contribute to promoting a more efficacious immune response against tumor target cells, thus showing a double therapeutic advantage.
Highlights
Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed serine/threonine kinase
Of interest are the results reported by Appleman et al that the pharmacological inactivation of glycogen synthase kinase-3 (GSK-3) by LiCl in human T cells substitutes for CD28, but not for CD3, a costimulatory signal for
In animal studies, the injection of GSK-3 inhibitors in mice suppressed PD-1 expression and increased T-bet expression in association with enhanced CD8+ CTL function [93]. These results suggest that GSK-3 inhibition may be an alternative approach to the use of antibodies against PD-1 in cancer immunotherapy
Summary
Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed serine/threonine kinase It is a multifunctional monomeric protein involved in various cellular functions, including differentiation [1], survival [2], glycogen metabolism [3,4], protein synthesis [5], immune responses [6], and cell death [7]. GSK-3β can regulate gene expression by activating or inhibiting some transcription factors, such as β-catenin, NF-κB, the nuclear factor of activated T cells (NFAT) [19], cyclic AMP response element binding protein (CREB) [20], c-Jun, and AP-1 [21]. Some studies have shown that active GSK-3 phosphorylates Notch, a GSK-3 target, preventing its degradation via the proteasome pathway, and as a result it is stabilized, promoting its enhanced nuclear localization and transcriptional activity [27]. Preclinical (in vitro and in vivo animal model experiments) and clinical studies were searched using relevant keywords in various databases, such as PubMed, ScienceDirect, SpringerLink, Scopus, Google Scholar, and ClinicalTrial.gov, as well as abstracts from international meetings (up to April 2020)
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