Cancer Letters

Cancer Letters

Volume 273, Issue 2, 18 January 2009, Pages 194-200
Cancer Letters

Mini-review
Glycogen synthase kinase 3β (GSK3β) in tumorigenesis and cancer chemotherapy

https://doi.org/10.1016/j.canlet.2008.05.045Get rights and content

Abstract

Glycogen synthase kinase 3β (GSK3β), a multifunctional serine/threonine kinase found in all eukaryotes, had been initially identified as a key regulator of insulin-dependent glycogen synthesis. It is now known that GSK3β functions in diverse cellular processes including proliferation, differentiation, motility and survival. Aberrant regulation of GSK3β has been implicated in a range of human pathologies including non-insulin-dependent diabetes mellitus, cardiovascular disease, some neurodegenerative diseases, and bipolar disorder. As a consequence, the therapeutic potential of GSK3β inhibitors has become an important area of investigation. However, GSK3β also participates in neoplastic transformation and tumor development. The role of GSK3β in tumorigenesis and cancer progression remains controversial; it may function as a “tumor suppressor” for certain types of tumors, but promotes growth and development for some others. GSK3β also mediates drug sensitivity/resistance in cancer chemotherapy. Therefore, although GSK3β is an attractive therapeutic target for a number of human diseases, its potential impact on tumorigenesis and cancer chemotherapy needs to be carefully evaluated. This mini-review discusses the role of GSK3β in tumorigenesis/cancer progression as well as its modulation of cancer chemotherapy.

Introduction

Glycogen synthase kinase 3 (GSK3) has become one of the most attractive therapeutic targets for the treatment of diabetes, inflammation, and multiple neurological diseases, including Alzheimer’s, stroke and bipolar disorders [1], [2]. GSK3 is a multifunctional serine/threonine kinase, originally found in mammals, and homologues have been found in all eukaryotes [3], [4]. GSK3 was first identified as a critical mediator in glycogen metabolism and insulin signaling. It is now known that GSK3 is an important component of diverse signaling pathways involved in the regulation of cell fate, protein synthesis, glycogen metabolism, cell mobility, proliferation and survival [3], [4]. There are two mammalian GSK3 isoforms encoded by distinct genes: GSK3α and GSK3β. The α and β isoforms share 85% identity [3]. The two genes map to human chromosomes 19q13.2 (GSK3α) and 3q13.3 (GSK3β). An elegant historical synopsis of the cloning and characterization of GSK3 genes has been reviewed by Plyte et al. [5]. Despite a high degree of similarity and functional overlap, these isoforms are not functionally identical and redundant. The signaling pathway and protein function of GSK3β are much better investigated. This review will focus on the action of GSK3β. Due to its diverse cellular functions, the pathways in which GSK3β acts as a key regulator, when dysregulated, have been implicated in the development of a number of human diseases such as diabetes, cardiovascular disease, some neurodegenerative diseases and bipolar disorder [3], [4], [6]. The dysregulation of GSK3β has also been implicated in tumorigenesis and cancer progression [7], [8], [9], [10]. However, the mechanisms underlying GSK3β regulation of neoplastic transformation and tumor development are unclear; it remains controversial whether GSK3β is a “tumor suppressor” or “tumor promoter.” This review will discuss the evidence that supports GSK3β as both “tumor suppressor” and “tumor promoter,” and the underlying mechanisms. In addition, the role of GSK3β in cancer chemotherapy will be briefly reviewed.

Section snippets

Regulation of GSK3β and its substrates

Unlike most protein kinases, GSK3β is constitutively active in resting cells and undergoes a rapid and transient inhibition in response to a number of external signals [3], [4]. GSK3β activity is regulated by site-specific phosphorylation. Full activity of GSK3β generally requires phosphorylation at tyrosine (Tyr216), and conversely, phosphorylation at serine (Ser9) inhibits GSK3β activity. GSK3β is subjected to multiple regulatory mechanisms and phosphorylation of Ser9 is probably the most

Involvement of GSK3β in tumorigenesis and cancer progression

Since GSK3β negatively regulates many proto-oncogenic proteins and cell cycle regulators, one would predict that GSK3β may suppress tumorigenesis. Several studies indeed support that GSK3β functions as a “tumor suppressor” and represses cellular neoplastic transformation and tumor development. GSK3β has been reported to be a negative regulator of skin tumorigenesis. In a mouse epidermal multistage carcinogenesis model, a dramatic increase in pGSK3β(Ser9) (inactive form of GSK3β) is observed in

Involvement of GSK3β in cancer chemotherapy

GSK3β also regulates cellular sensitivity/resistance to cancer chemotherapy. Increased expression of pGSK3β(Ser9) is observed in cisplatin-resistant ovarian cancer cell line (CP70) compared to its cisplatin-sensitive counterpart A2780 cells [40]. High pGSK3β(Ser9) levels in CP70 cells suggest that suppressed GSK3β activity may account for their resistance to cisplatin. Inhibition of GSK3β by treatment with lithium significantly reduces cisplatin-induced apoptosis and raises the IC50 of

The mechanisms of GSK3β action

Since GSK3β regulates diverse substrates and signaling pathways, the mechanisms underlying its anti-tumor or pro-tumor action are complex. One of the most important impacts of GSK3β on neoplastic transformation tumor development is likely mediated by its influence on Wnt/β-catenin signaling. Phosphorylation of β-catenin by active GSK3β targets β-catenin for ubiquitin-mediated proteasomal degradation and maintains a low level of cytoplasmic β-catenin. Activation of Wnt signaling inhibits GSK3β

Conclusion

GSK3β has emerged as one of the most attractive therapeutic targets for the treatment of some neurological diseases, including Alzheimer’s, stroke and bipolar disorders, as well as diabetes and inflammation. Recently, GSK3β has been viewed as a viable target in the treatment of several human neoplasms due to its involvement in tumor development and chemoresistance. However, it remains controversial whether GSK3β is a “tumor suppressor” or “tumor promoter.” Available evidence indicates that

Acknowledgements

I would like to thank Kimberly A. Bower for reading this manuscript. This research was supported by grants from the National Institutes of Health (AA015407 and AA017226).

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