GSK-3 as potential target for therapeutic intervention in cancer

Abstract

The serine/threonine kinase glycogen synthase kinase-3 (GSK-3) was initially identified and studied in the regulation of glycogen synthesis. GSK-3 functions in a wide range of cellular processes. Aberrant activity of GSK-3 has been implicated in many human pathologies including: bipolar depression, Alzheimer's disease, Parkinson's disease, cancer, non-insulin-dependent diabetes mellitus (NIDDM) and others. In some cases, suppression of GSK-3 activity by phosphorylation by Akt and other kinases has been associated with cancer progression. In these cases, GSK-3 has tumor suppressor functions. In other cases, GSK-3 has been associated with tumor progression by stabilizing components of the beta-catenin complex. In these situations, GSK-3 has oncogenic properties. While many inhibitors to GSK-3 have been developed, their use remains controversial because of the ambiguous role of GSK-3 in cancer development. In this review, we will focus on the diverse roles that GSK-3 plays in various human cancers, in particular in solid tumors. Recently, GSK-3 has also been implicated in the generation of cancer stem cells in various cell types. We will also discuss how this pivotal kinase interacts with multiple signaling pathways such as: PI3K/PTEN/Akt/mTORC1, Ras/Raf/MEK/ERK, Wnt/beta-catenin, Hedgehog, Notch and others.

Therapeutic Innovations for Targeting Hepatoblastoma

“…Particularly, the cytoplasmic domain of Ecadherin contains several phosphorylation sites for CKII and GSK3β (131). However, we found an increase of AKTdependent phosphorylation of GSK3β (S9), which is known to completely suppress its kinase activity (132). Therefore, it is unlikely that GSK3β is responsible for the observed effect.…”

Nine-month follow-up of the insulin receptor signalling cascade in the brain of streptozotocin rat model of sporadic Alzheimer’s disease

“…Such a change in the GSK-3β activity seems not to correlate with alterations in the IR protein level in that period (decreased expression) but since we have not measured the IR tyrosine kinase activity, it could not be excluded that it might be increased at this time point to compensate for reduced IR protein level and consequently to lead to such changes in p/t GSK-3β ratio (activity). Additionally, it has to be kept in mind that GSK-3β phosphorylation homeostasis might be affected by different kinases besides IR-PI-3K-Akt/PKB pathway, like ERK which can phosphorylate GSK-3β on T48 site making GSK-3 β inactive, as regulated through IR-MAPK pathway (McCubrey et al 2014). This speculation might be a possible explanation also of the tau hyperphoshorylation (PHF1) we observed in the period of 1-3 months after STZ-icv administration when GSK-3β activity was not increased.…”

The MITF family of transcription factors: Role in endolysosomal biogenesis, Wnt signaling, and oncogenesis

“…Inhibiting GSK3 activity with small molecules may be considered a double-edged sword as it could stimulate malignant transformation and cancer growth by activating Wnt/␤-Catenin signaling or by stabilizing oncogenes regulated by Wnt/STOP such as c-Jun and c-Myc [6,11]. However, long-term studies in mice treated with GSK3 inhibitors have not revealed oncogenic effects [97]. Additionally, the GSK3 inhibitor Lithium Chloride, which has long been used to treat patients with bipolar disorder, has never been linked to increased cancer incidence [97].…”

“…However, long-term studies in mice treated with GSK3 inhibitors have not revealed oncogenic effects [97]. Additionally, the GSK3 inhibitor Lithium Chloride, which has long been used to treat patients with bipolar disorder, has never been linked to increased cancer incidence [97]. In fact, it has been observed that GSK3 inhibitors can decrease cellular proliferation of some cancers, including melanoma, prostate, and pancreatic tumors [98,99].…”