Mini-reviewGlycogen synthase kinase 3β (GSK3β) in tumorigenesis and 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).
References (59)
- et al.
The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling
Prog. Neurobiol.
(2001) - et al.
The paradoxical pro- and anti-apoptotic actions of GSK3 in the intrinsic and extrinsic apoptosis signaling pathways
Prog. Neurobiol.
(2006) Primers on molecular pathways. The glycogen synthase kinase-3beta
Pancreatology
(2007)- et al.
Role of glycogen synthase kinase-3 in cancer: regulation by Wnts and other signaling pathways
Adv. Cancer Res.
(2002) - et al.
Glycogen synthase kinase 3beta is tyrosine phosphorylated by PYK2
Biochem. Biophys. Res. Commun.
(2001) - et al.
Transient increases in intracellular calcium result in prolonged site-selective increases in Tau phosphorylation through a glycogen synthase kinase 3beta-dependent pathway
J. Biol. Chem.
(1999) - et al.
Glycogen synthase kinase-3beta is tyrosine-phosphorylated by MEK1 in human skin fibroblasts
Biochem. Biophys. Res. Commun.
(2004) - et al.
The eIF2alpha kinases PERK and PKR activate glycogen synthase kinase 3 to promote the proteasomal degradation of p53
J. Biol. Chem.
(2007) - et al.
The role of epithelial–mesenchymal transition in cancer pathology
Pathology
(2007) - et al.
Expression of cyclooxygenase-2 is regulated by glycogen synthase kinase-3beta in gastric cancer cells
J. Biol. Chem.
(2006)
Deregulated GSK3beta activity in colorectal cancer: its association with tumor cell survival and proliferation
Biochem. Biophys. Res. Commun.
Inhibition of glycogen synthase kinase-3 activity leads to epigenetic silencing of nuclear factor kappaB target genes and induction of apoptosis in chronic lymphocytic leukemia B cells
Blood
GSK-3beta inhibition by lithium confers resistance to chemotherapy-induced apoptosis through the repression of CD95 (Fas/APO-1) expression
Exp. Cell. Res.
c-fos is required for malignant progression of skin tumors
Cell
Phosphatidylinositol-3 kinase is necessary for 12-O-tetradecanoylphorbol-13-acetate-induced cell transformation and activated protein 1 activation
J. Biol. Chem.
NF-kappaB: tumor promoter or suppressor?
Trends Cell Biol.
Inhibition of GSK-3beta mediates expression of MMP-9 through ERK1/2 activation and translocation of NF-kappaB in rat primary astrocyte
Brain Res.
Glycogen synthase kinase-3 (GSK3): inflammation, diseases, and therapeutics
Neurochem. Res.
Physiological roles of glycogen synthase kinase-3: potential as a therapeutic target for diabetes and other disorders
Curr. Drug Targets Immune Endocr. Metabol. Disord.
GSK-3: tricks of the trade for a multi-tasking kinase
J. Cell Sci.
Glycogen synthase kinase-3: functions in oncogenesis and development
Biochim. Biophys. Acta
Targeting GSK-3: a promising approach for cancer therapy?
Future Oncol.
CK2 as a positive regulator of Wnt signalling and tumourigenesis
Mol. Cell. Biochem.
Insulin transiently increases tau phosphorylation: involvement of glycogen synthase kinase-3beta and Fyn tyrosine kinase
J. Neurochem.
The Wnt signaling pathway and its role in tumor development
J. Cancer Res. Clin. Oncol.
Expression, localization, and activity of glycogen synthase kinase 3beta during mouse skin tumorigenesis
Mol. Carcinog.
Myeloid cell leukemia-1 inversely correlates with glycogen synthase kinase-3beta activity and associates with poor prognosis in human breast cancer
Cancer Res.
The role of glycogen synthase kinase 3beta in the transformation of epidermal cells
Cancer Res.
Kinase-inactive glycogen synthase kinase 3beta promotes Wnt signaling and mammary tumorigenesis
Cancer Res.
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