Glycogen synthase kinase 3β in tumorigenesis and oncotherapy (Review)

Abstract

Glycogen synthase kinase 3β (GSK 3β), a multifunctional serine and threonine kinase, plays a critical role in a variety of cellular activities, including signaling transduction, protein and glycogen metabolism, cell proliferation, cell differentiation, and apoptosis. Therefore, aberrant regulation of GSK 3β results in a broad range of human diseases, such as tumors, diabetes, inflammation and neurodegenerative diseases. Accumulating evidence has suggested that GSK 3β is correlated with tumorigenesis and progression. However, GSK 3β is controversial due to its bifacial roles of tumor suppression and activation. In addition, overexpression of GSK 3β is involved in tumor growth, whereas it contributes to the cell sensitivity to chemotherapy. However, the underlying regulatory mechanisms of GSK 3β in tumorigenesis remain obscure and require further in‑depth investigation. In this review, we comprehensively summarize the roles of GSK 3β in tumorigenesis and oncotherapy, and focus on its potentials as an available target in oncotherapy.

Keywords: glycogen synthase kinase 3β; tumorigenesis; oncotherapy; GSK 3β inhibitors.

Figure 1.

Functional domains and tertiary structures of GSK 3β (Homo sapiens). GSK 3β is a 47-kDa protein consisting of 433 amino-acids in human. The protein contains an N-terminal domain, kinase domain and C-terminal domain. Phosphorylation at Tyrosine (216) in the N-terminal region of GSK 3β activates this kinase. Phosphorylation at Serine (9) in the N-terminal region of GSK 3β leads to the inactivation of this kinase. The BD includes GSK 3β specific binding sites for substrates and protein complexes. GSK 3β, glycogen synthase kinase 3β; BD, binding domain.

Figure 2.

Regulatory mechanisms of GSK 3β. The activity of GSK 3β can be inactivated by multiple pathways. PI3K/Akt, P70S6K, p90sk, ERKs and PKA/PKC can attenuate GSK 3β enzymatic activity by phosphorylating GSK 3β at Ser9. Inhibition of GSK 3β activity leads to the stabilization and accumulation of β-catenin in the cytosol. GSK 3β inactivation is also involved in glycogen synthesis, protein synthesis, cell proliferation and cell invasion. Additionally, PYK2, Ca²⁺, ZAK1 and Fyn are able to phosphorylate GSK 3β at Tyr216, which increases the GSK 3β activity. Subsequently, activated GSK 3β phosphorylates downstream target β-catenin. GSK 3β, glycogen synthase kinase3β; PI3K, phosphoinositide3 kinase; P70S6K, P70S6 kinase; ERKs, extracellular signal-regulated kinases; PKC, protein kinase C; PKA, protein kinase A; HKII, hexokinase II; AP-1, activating protein-1; MDM2, murine double minute 2; PYK2, proline-rich tyrosine kinase 2; ZAK1, Zaphod kinase 1; APC, adenomatous polyposis coli.

Figure 3.

GSK 3β regulates the key signaling proteins of the Wnt pathway. In the presence of Wnt, β-catenin is stabilized and can induce gene transcription. Wnt binds with its co-receptors Frizzled and LRP5/LRP6. Axin and APC interact with phosphorylated GSK 3β at Tyr216, which leads to β-catenin stabilization and cytosol accumulation. Subsequently, β-catenin is transferred into the nucleus where it activates the transcription of related genes by forming a complex with transcription factors as TCF/LEF. Then, TCF/LEF upregulates the proto-oncogenes (c-Myc and cyclin D1) and cell invasion/migration-related genes (MMP-7 and Cdc37). GSK 3β, glycogen synthase kinase 3β; APC, adenomatous polyposis coli; TCF, T-cell factor; LEF, lymphocyte enhancer factor; MMP-7, matrix metalloproteinase-7.

Figure 4.

Tumor inhibitory role of GSK 3β. LY294002, adiponectin and PTEN suppress GSK 3β-participated β-catenin degradation and cell cycle arrest by inhibiting the PI3K/Akt pathway in prostate tumor and breast cancer. The deletion of MIF attenuates Akt-dependent GSK 3β phosphorylation and restores tumor suppressor activity of GSK 3β in esophageal squamous cell carcinoma. Additionally, GSK 3β phosphorylates various tumor factors, facilitates their degradation, and prevents them from entering the nucleus. GSK 3β, glycogen synthase kinase 3β; PTEN, phosphatase and tension homolog deleted on chromosome 10; AR, androgen receptor; CCND1, cyclin D1 gene; FAK, focal adhesion kinase; MMPs, matrix metalloproteinases; AP-1, activating protein-1.

Figure 5.

Molecular pathways revealing how GSK 3β influences tumor sensitivity to different chemo-therapeutic agents. In glioblastoma, GSK 3β inhibition improves temozolomide sensitivity by regulating the Mdm2/P53 and c-Myc/MGMT signaling pathways, which upregulate the methylation of MGMT promoter. Additionally, GSK 3β inhibitor enhances the sensitivity of pancreatic cancer to gemcitabine by negatively regulating the cyclin D1/CDK4/6 complex-dependent phosphorylation of Rb tumor suppressor protein. GSK 3β, glycogen synthase kinase 3β; DNMT3A, DNA methyltransferase 3 alpha; Mdm2, mouse double minute 2; MGMT, O⁶-methylguanine DNA methyl transferase; TP53INP1, tumor protein 53-induced-nuclear-protein 1; IR, ionizing radiation; 53BP1, p53 binding protein 1; CDK 4/6, cyclin-dependent kinase 4/6; Rb, retinoblastoma; E2F, E2 transcription factor.