Effects Of Glycogen Synthase Kinase-3 Research Articles

GSK-3β Can Regulate the Sensitivity of MIA-PaCa-2 Pancreatic and MCF-7 Breast Cancer Cells to Chemotherapeutic Drugs, Targeted Therapeutics and Nutraceuticals.

Glycogen synthase kinase-3 (GSK-3) is a regulator of signaling pathways. KRas is frequently mutated in pancreatic cancers. The growth of certain pancreatic cancers is KRas-dependent and can be suppressed by GSK-3 inhibitors, documenting a link between KRas and GSK-3. To further elucidate the roles of GSK-3β in drug-resistance, we transfected KRas-dependent MIA-PaCa-2 pancreatic cells with wild-type (WT) and kinase-dead (KD) forms of GSK-3β. Transfection of MIA-PaCa-2 cells with WT-GSK-3β increased their resistance to various chemotherapeutic drugs and certain small molecule inhibitors. Transfection of cells with KD-GSK-3β often increased therapeutic sensitivity. An exception was observed with cells transfected with WT-GSK-3β and sensitivity to the BCL2/BCLXL ABT737 inhibitor. WT-GSK-3β reduced glycolytic capacity of the cells but did not affect the basal glycolysis and mitochondrial respiration. KD-GSK-3β decreased both basal glycolysis and glycolytic capacity and reduced mitochondrial respiration in MIA-PaCa-2 cells. As a comparison, the effects of GSK-3 on MCF-7 breast cancer cells, which have mutant PIK3CA, were examined. KD-GSK-3β increased the resistance of MCF-7 cells to chemotherapeutic drugs and certain signal transduction inhibitors. Thus, altering the levels of GSK-3β can have dramatic effects on sensitivity to drugs and signal transduction inhibitors which may be influenced by the background of the tumor.

GABA mediates NO/cGMP/GSK-3-induced isoflavone accumulation in soybean sprouts

The effects of glycogen synthase kinase-3 (GSK-3) on nitric oxide (NO)/guanosine 3′,5′-cyclic monophosphate (cGMP)-activated γ-aminobutiric acid (GABA) accumulation and the role of GABA in isoflavone biosynthesis in response to UV-B exposure in soybean sprouts were investigated. The sprouts were sprayed using donors and inhibitors of cGMP and NO as well as inhibitors of GSK-3 and GABA. It turned out that GSK-3, as a second messenger, mediated NO/cGMP/PKG-induced GABA accumulation by activating diamine oxidase (DAO) under UV-B treatment. GABA mediated NO/cGMP/PKG/GSK-3-stimulated the increment of gene and protein expression and activity of chalcone synthase (CHS) and isoflavone synthase (IFS), and consequently induced the elevation in isoflavone content. Overall, GABA mediates NO/cGMP/PKG/GSK-3-stimulated isoflavone production in response to UV-B exposure in soybean sprouts.

A hypothetic role of minocycline as a neuroprotective agent against methylphenidate-induced neuronal mitochondrial dysfunction and tau protein hyper-phosphorylation: Possible role of PI3/Akt/GSK3β signaling pathway

The underlining mechanism in neural mitochondrial dysfunction and consequences neurotoxicity, and cognitive behavior after methylphenidate (MPH) prolonged uses is unclear and proposing of therapeutic approaches for treatment of these types of neurotoxicity is one of the main goals of scientist in this manner. MPH-induced mitochondrial dysfunction in neural cells caused induction of oxidative stress, apoptosis, inflammation and cognition impairment, which leads to neurotoxicity, was reported previously but role of key neural cells proteins and involved signaling pathway in this manner remained indeterminate. Tau protein aggregation is a biomarker for mitochondrial dysfunction, neurodegenerative event and cognition impairment. Tau aggregation occur by stimulation effects of Glycogen synthase kinase-3(GSK3β) and phosphatidylinositol 3-kinase (PI3K) which activates protein kinase B(Akt) and causes inhibition of phosphorylation(activation) of GSK3β, thus Akt activation can cause inhibition of tau aggregation (hyper-phosphorylation). Management of mentioned MPH-induced mitochondrial dysfunction and consequences of neurotoxicity, and cognitive behavior through a new generation neuroprotective combination, based on modulation of disturbed in Akt function and inhibition of GSK3β and tau hyper-phosphorylation can be a prefect therapeutic interventions. Therefore, finding, introduction and development of new neuroprotective properties and explanation of their effects with potential capacity for modulation of tau hyper-phosphorylation via PI3/Akt/GSK signaling pathway is necessitated. During recent years, using new neuroprotective compounds with therapeutic probability for treatment of psychostimulant-induced mitochondrial dysfunction, neurotoxicity and cognitive malicious effects have been amazingly increased. Many previous studies have reported the neuroprotective roles of minocycline (a broad-spectrum and long-acting antibiotic) in multiple neurodegenerative events and diseases in animal model. But the role of neuroprotective effects of this agent against MPH induced mitochondrial dysfunction, neurotoxicity and cognitive malicious and also role of tau hyper-phosphorylation by modulation of PI3/Akt/GSK signaling pathway in this manner remain unknown. Thus we suggested and theorized that by using minocycline in MPH addicted subject, it would provide neuroprotection against MPH-induced mitochondrial dysfunction, neurotoxicity and cognitive malicious. Also we hypothesized that minocycline, via modulation of PI3/Akt/GSK and inhibition of tau hyper-phosphorylation, can inhibit MPH-induced mitochondrial dysfunction, neurotoxicity and cognitive malicious. In this article, we tried to discuss our hypothesis regarding the possible role of minocycline, as a powerful neuroprotective agent, and also role of tau hyper-phosphorylation related to PI3/Akt/GSK signaling pathway in treatment of MPH-induced mitochondrial dysfunction, neurotoxicity and cognitive disturbance.

Effects of Glycogen Synthase Kinase Inhibitor on Glioblastoma Multiforme Cell Line via Apoptosis and Cell Signaling Pathways.

To investigate the apoptotic and molecular effects of glycogen synthase kinase-3 (GSK-3) in glioblastoma multiforme (GBM). Human primary glioblastoma cell line (U-87 MG) and the human fetal glial cell line (SVGp12) were used. The cells were exposed to the different doses of GSK inhibitor for 24, 48 and 72 hours. Induction of apoptosis was assessed by DNA fragmentation (TUNEL) assay. EGFR and NF-kB expression was evaluated by immunofluorescence analyses. GSK-3 inhibitor IX induced cytotoxicity and apoptosis in dose-dependent manner in GBM cells. Our results indicated that GSK-3 inhibitor IX induces apoptosis, resulting in a significant decrease in the expression of NF-kB and EGF. Inhibition through GSK-3 has been found promising in creating therapeutic management of GBM cells. Proliferation, differentiation, cell cycle regulation, and apoptosis are mechanisms that must be interpreted as a whole. Components associated with EGFR, NF-kB, and apoptosis affect the mechanism solely and collectively. Our collective data suggest that GSK-3 inhibitor IX inhibited cellular proliferation and induced apoptotic events by modulating EGFR and NF-kB expression in GBM cells. GSK-3 inhibition holds promise for the development of new approaches for the therapeutic management of GBM cells.

Glycogen synthase kinase 3 in the world of cell migration

Glycogen synthase kinase 3 (GSK3) is one of the few master switch kinases that regulate many aspects of cell functions. Recent studies on cell polarization and migration have shown that GSK3 is also essential for proper regulation of these processes. GSK3 influences cell migration as one of the regulators of the spatiotemporally controlled dynamics of the actin cytoskeleton, microtubules, and cell-to-matrix adhesions. In this mini-review, the effects of GSK3 on these three aspects of cell migration will be discussed.

Glycogen synthase kinase‐3 negatively regulates anti‐inflammatory interleukin‐10 for lipopolysaccharide‐induced iNOS/NO biosynthesis and RANTES production in microglial cells

The inflammatory effects of glycogen synthase kinase-3 (GSK-3) have been identified; however, the potential mechanism is still controversial. In this study, we investigated the effects of GSK-3-mediated interleukin-10 (IL-10) inhibition on lipopolysaccharide (LPS)-induced inflammation. Treatment with GSK-3 inhibitor significantly blocked LPS-induced nitric oxide (NO) production as well as inducible NO synthase (iNOS) expression in BV2 murine microglial cells and primary rat microglia-enriched cultures. Using an antibody array and enzyme-linked immunosorbent assay, we found that GSK-3-inhibitor treatment blocked LPS-induced upregulation of regulated on activation normal T-cell expressed and secreted (RANTES) and increased IL-10 expression. The time kinetics and dose-response relations were confirmed. Reverse transcription-polymerase chain reaction showed changes on the messenger RNA level as well. Inhibiting GSK-3 using short-interference RNA, and transfecting cells with dominant-negative GSK-3beta, blocked LPS-elicited NO and RANTES expression but increased IL-10 expression. In contrast, GSK-3beta overexpression upregulated NO and RANTES but downregulated IL-10 in LPS-stimulated cells. Treating cells with anti-IL-10 neutralizing antibodies to prevent GSK-3 from downregulating NO and RANTES showed that the anti-inflammatory effects are, at least in part, IL-10-dependent. The involvement of Akt, extracellular signal-regulated kinase, p38 mitogen-activated protein kinase and nuclear factor-kappaB that positively regulated IL-10 was demonstrated. Furthermore, inhibiting GSK-3 increased the nuclear translocation of transcription factors, that all important for IL-10 expression, including CCAAT/enhancer-binding protein beat (C/EBPbeta), C/EBPdelta, cAMP response binding element protein and NF-kappaB. Taken together, these findings reveal that LPS induces iNOS/NO biosynthesis and RANTES production through a mechanism involving GSK-3-mediated IL-10 downregulation.

IFN-γ synergizes with LPS to induce nitric oxide biosynthesis through glycogen synthase kinase-3-inhibited IL-10

Interferon-gamma (IFN-gamma) plays a crucial role in innate immunity and inflammation. It causes the synergistic effect on endotoxin lipopolysaccharide (LPS)-stimulated inducible nitric oxide synthase (iNOS)/NO biosynthesis; however, the mechanism remains unclear. In the present study, we investigated the effects of glycogen synthase kinase-3 (GSK-3)-mediated inhibition of anti-inflammatory interleukin-10 (IL-10). We found, in LPS-stimulated macrophages, that IFN-gamma increased iNOS expression and NO production in a time-dependent manner. In addition, ELISA analysis showed the upregulation of tumor necrosis factor-alpha and regulated on activation, normal T expressed and secreted, and the downregulation of IL-10. RT-PCR further showed changes in the IL-10 mRNA level as well. Treating cells with recombinant IL-10 showed a decrease in IFN-gamma/LPS-induced iNOS/NO biosynthesis, whereas anti-IL-10 neutralizing antibodies enhanced this effect, suggesting that IL-10 acts in an anti-inflammatory role. GSK-3-inhibitor treatment blocked IFN-gamma/LPS-induced iNOS/NO biosynthesis but upregulated IL-10 production. Inhibiting GSK-3 using short-interference RNA showed similar results. Additionally, treating cells with anti-IL-10 neutralizing antibodies blocked these effects. We further showed that inhibiting GSK-3 increased phosphorylation of transcription factor cyclic AMP response element binding protein. Inhibiting protein tyrosine kinase Pyk2, an upstream regulator of GSK-3beta, caused inhibition on IFN-gamma/LPS-induced GSK-3beta phosphorylation at tyrosine 216 and iNOS/NO biosynthesis. Taken together, these findings reveal the involvement of GSK-3-inhibited IL-10 on the induction of iNOS/NO biosynthesis by IFN-gamma synergized with LPS.

Inhibition of GSK-3 reduces infarct volume and improves neurobehavioral functions

In the present study, we have investigated the effects of glycogen synthase kinase-3 (GSK-3) inhibition on infarct volume and neurobehavioral functions in a focal cerebral ischemia model. To achieve our goals, GSK-3 inhibitor II or VIII was injected at several time points and in varing dosages. GSK-3 inhibitor VIII was more effective than inhibitor II, and infarct volume and water content in the VIII group were significantly decreased 24 h after the onset of ischemic stroke, as compared with the control group. These protective effects were associated with reductions of TUNEL-positive cells, neutrophil infiltration, glucose levels after ischemia, and GSK-3 enzyme activity. In addition, expressions of death and inflammation-related signals decreased and those of survival-related signals increased. Lastly, neurobehavioral functions were restored to a greater extent in the VIII group than in the control group. Together, these results suggest that GSK-3 inhibition reduces infarct volume and restores neurobehavioral functions.

Effects of glycogen synthase kinase-3[beta] inhibition on the development of cerulein-induced acute pancreatitis in mice *

Effects of glycogen synthase kinase-3[beta] inhibition on the development of cerulein-induced acute pancreatitis in mice *

Glycogen Synthase Kinase-3 Modulates Neurite Outgrowth in Cultured Neurons: Possible Implications for Neurite Pathology in Alzheimer's Disease.

Glycogen synthase kinase-3 (GSK-3) is thought to play an important role in the hyperphosphorylation of tau, and possibly other proteins, in Alzheimer's disease (AD). However, the effects of GSK-3 on neuronal metabolism are still largely unknown. Here we describe that a low concentration of lithium, which can partially inhibit endogenous GSK-3, favored the extension of neurites from developing neurons, whereas a high concentration of lithium impaired neurite growth. Furthermore, the overexpression of exogenous active GSK-3 in neurons by infection with a defective herpesviral vector blocked neurite growth, which was not affected by either expression of inactive GSK-3 or just the herpesviral vector infection. Neurite extension was restored when neurons overexpressing exogenous active GSK-3 were incubated with lithium. These results are consistent with a role for GSK-3 in the regulation of cytoskeletal dynamics during neurite growth. Accordingly, up-regulation of GSK-3 may contribute to cytoskeletal pathology within neurites in AD.