Glycogen synthase kinase 3 beta: can it be a target for oral cancer

Abstract

Despite progress in treatment approaches for oral cancer, there has been only modest improvement in patient outcomes in the past three decades. The frequent treatment failure is due to the failure to control tumor recurrence and metastasis. These failures suggest that new targets should be identified to reverse oral epithelial dysplastic lesions. Recent developments suggest an active role of glycogen synthase kinase 3 beta (GSK3 beta) in various human cancers either as a tumor suppressor or as a tumor promoter. GSK3beta is a Ser/Thr protein kinase, and there is emerging evidence that it is a tumor suppressor in oral cancer. The evidence suggests a link between key players in oral cancer that control transcription, accelerated cell cycle progression, activation of invasion/metastasis and anti-apoptosis, and regulation of these factors by GSK3beta. Moreover, the major upstream kinases of GSK3beta and their oncogenic activation by several etiological agents of oral cancer support this hypothesis. In spite of all this evidence, a detailed analysis of the role of GSK3beta in oral cancer and of its therapeutic potential has yet to be conducted by the scientific community. The focus of this review is to discuss the multitude of roles of GSK3beta, its possible role in controlling different oncogenic events and how it can be targeted in oral cancer.

Figure 1

Progressive inactivation of GSK3β may promote accelerated cell cycle and oral cancer. As discussed in the text, most of the cell cycle regulators and their gain of function may be because of inactivation of GSK3β in oral cancer. GSK3β regulates the activity or turnover of several master cell cycle regulators like p53. Activation of p21, 14-3-3σ and GADD45 protein by p53 induces cell cycle arrest to prevent the propagation of mutations, which accumulate in cells under genotoxic stress. p53 induces the expression of the cytoplasmic scaffold protein 14-3-3σ, which prevents the nuclear import of cyclin B1 and cdc2 by sequestration in the cytoplasm. On the other hand, GADD45 destabilizes CDC2/cyclinB complexes. GSK3β-regulated c-Myc is a master regulator of the cell cycle and is essential for G0/G1-to-S progression. Myc suppresses the expression of cell cycle checkpoint genes (GADD45, GADD153) and inhibits the function of CDK inhibitors. Myc also activates cyclins D1, E1, and A2, CDK4, CDC25A, and E2F-1 and -2. Cyclin D1 is a crucial cell cycle regulator mainly regulated by the activity of TFs (NFκB, β-catenin-TCF/LEF, AP-1) and is indirectly controlled by GSK3β. Moreover, inactivation of GSK3β leads to the stabilization of cyclin D1. Oncogenic gains of function of these molecules stemming from inactive GSK3β have been established in various neoplastic diseases and might orchestrate cell cycle dysregulation in OSCC.

Figure 2

Progressive inactivation of GSK3β may promote enhanced EMT and oral cancer. GSK3β regulates several molecules that participate in epithelial-mesenchymal transformation, invasion and metastasis in cancer. Normal epithelial cells are connected to each other by E-cadherin, which binds to α- and β-catenin, which in turn connect E-cadherin to the actin cytoskeleton. Levels of E-cadherin are decreased in EMT. E-cadherin expression is suppressed by Snail. MMPs degrade the BM and facilitate the migration of cancer cells. Several MMPs upregulated and activated in OSCC are controlled by TFs such as Snail, AP-1, and NFκB. All of these events are directly or indirectly linked to the inactivation status of GSK3β.

Figure 3

Progressive inactivation of GSK3β may promote increased anti-apoptosis and oral cancer. GSK3β-mediated signaling controls apoptosis in OSCC. In the intrinsic apoptotic pathway, inactive GSK3β fails to promote apoptosis by the disruption of mitochondrial membrane potential resulting from disruption of the Bcl-2/Bax ratio. Overexpression of Bcl-2 and suppression of Bax occur frequently in OSCC. This may be due to either inactive p53 (in the subgroup of cases in which p53 is not mutated or silenced) or active CREB; both are controlled by GSK3β. In the extrinsic pathway, active GSK3β promotes apoptosis by inducing procaspase-8 activation. Moreover, the inactivated GSK3β might send survival signals via the extrinsic pathway by blocking procaspase-8 activation in OSCC. By doing this, GSK3β might maintain the balance between proliferation and death and contribute to tissue homeostasis in normal oral epithelium; these might be perturbed in OSCC.

Figure 4

Targeting GSK3β pathway may be highly beneficial for curing oral cancer. Inhibition of GSK3β activity by the activation of several oncogenic pathways in cancer as discussed in the text. Activation of these pathways by several oral cancer etiological factors is interesting and fuel for inactivating GSK3β by targeting its inactivating pathways to promote oral cancer. Two major therapeutic strategies may be adopted to keep GSK3β active. First and the most important will be to (---) prevent the inactivation of GSK3β, by targeting its upstream inhibitory kinases, so that they will remain unassociated. Second will be to (---) reconstitute the active GSK3β (Ala9GSK3β by gene therapy) to affected oral cancer sites.