Targeting GSK3 and Associated Signaling Pathways Involved in Cancer

Cells, Journal Year: 2020, Volume and Issue: 9(5), P. 1110 - 1110

Published: April 30, 2020

Glycogen synthase kinase 3 (GSK-3) is a serine/threonine (S/T) protein kinase. Although GSK-3 originally was identified to have functions in regulation of glycogen synthase, it subsequently determined roles multiple normal biochemical processes as well various disease conditions. sometimes referred moonlighting due the substrates and which controls. Frequently, when phosphorylates proteins, they are targeted for degradation. often considered component PI3K/PTEN/AKT/GSK-3/mTORC1 pathway frequently phosphorylated by AKT regulates its inactivation. active human cancer hence, inactivated. Moreover, also interacts with WNT/β-catenin signaling β-catenin other proteins this targets GSK-3. can modify NF-κB activity expressed at high levels cells. Multiple pharmaceutical companies developed small molecule inhibitors suppress activity. In addition, natural products will This review focus on effects provide examples where these compounds were effective suppressing growth.

Language: Английский

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NRF2 activation promotes the recurrence of dormant tumour cells through regulation of redox and nucleotide metabolism

Nature Metabolism, Journal Year: 2020, Volume and Issue: 2(4), P. 318 - 334

Published: April 20, 2020

Language: Английский

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Targeting GSK3 signaling as a potential therapy of neurodegenerative diseases and aging

Expert Opinion on Therapeutic Targets, Journal Year: 2018, Volume and Issue: 22(10), P. 833 - 848

Published: Sept. 22, 2018

Glycogen synthase kinase 3 (GSK3) is at the center of cellular signaling and controls various aspects brain functions, including development nervous system, neuronal plasticity onset neurodegenerative disorders. Areas covered: In this review, recent efforts in elucidating roles GSK3 pathologies; Alzheimer's Parkinson's disease, schizophrenia, age-related neurodegeneration are described. The effect microglia astrocytes on pathological states also discussed. Expert opinion: GSK3β its pathway partners hold great promise as therapeutic target(s) for a multitude neurological Activity often elevated However, due to wide range targets, global inhibition leads severe side-effects inhibitors rarely reach Phase-2 clinical trials. Thus, selective modulation specific pool or down- upstream might provide more efficient anti-neurodegenerative therapies.

Language: Английский

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Nimbolide, a neem limonoid inhibits cytoprotective autophagy to activate apoptosis via modulation of the PI3K/Akt/GSK-3β signalling pathway in oral cancer

Cell Death and Disease, Journal Year: 2018, Volume and Issue: 9(11)

Published: Oct. 23, 2018

Abstract Of late, nimbolide, a limonoid from the neem tree ( Azadirachta indica ) has gained increasing research attention owing to its potent antiproliferative and apoptosis-inducing effects. The present study was designed investigate effect of nimbolide on autophagy time point at which phosphorylation status GSK-3β PI3K dictate choice between apoptosis in SCC131 SCC4 oral cancer cells. Additionally, we analysed changes expression proteins involved after therapeutic intervention with hamster model oncogenesis. Furthermore, also demonstrate key genes during stepwise evolution human OSCCs. Nimbolide-induced stereotypical cells characteristic both autophagy. Time-course experiments revealed that induces as an early event then switches over apoptosis. Nimbolide negatively regulates PI3K/Akt signalling consequent increase p-GSK-3β Tyr216 , active form inhibits Downregulation HOTAIR, competing endogenous RNA sponges miR-126 may be major contributor inactivation PI3K/Akt/GSK3 by nimbolide. Analysis markers well p-Akt Ser473 sequential progression OSCC gradual pro-autophagic antiapoptotic phenotype could confer survival advantage tumors. In summary, results provide insights into molecular mechanisms augments overcoming shielding effects cytoprotective through modulation Akt ncRNAs HOTAIR. Development phytochemicals such target complex interaction regulate autophagy/apoptosis flux is paramount importance prevention therapeutics.

Language: Английский

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Glycogen Synthase Kinase 3β in Cancer Biology and Treatment

Cells, Journal Year: 2020, Volume and Issue: 9(6), P. 1388 - 1388

Published: June 3, 2020

Glycogen synthase kinase (GSK)3β is a multifunctional serine/threonine protein with more than 100 substrates and interacting molecules. GSK3β normally active in cells negative regulation of activity via phosphorylation its serine 9 residue required for most normal to maintain homeostasis. Aberrant expression contributes the pathogenesis progression common recalcitrant diseases such as glucose intolerance, neurodegenerative disorders cancer. Despite recognized roles against several proto-oncoproteins mediators epithelial–mesenchymal transition, deregulated also participates tumor cell survival, evasion apoptosis, proliferation invasion, well sustaining cancer stemness inducing therapy resistance. A therapeutic effect from inhibition has been demonstrated 25 different types. Moreover, there increasing evidence that protects tissues harmful effects associated conventional therapies. Here, we review supporting aberrant hallmark property highlight beneficial on during therapy. The biological rationale targeting treatment discussed at length.

Language: Английский

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Glycogen synthase kinase-3 beta inhibitors as novel cancer treatments and modulators of antitumor immune responses

Cancer Biology & Therapy, Journal Year: 2019, Volume and Issue: 20(8), P. 1047 - 1056

Published: April 12, 2019

As a kinase at the crossroads of numerous metabolic and cell growth signaling pathways, glycogen synthase kinase-3 beta (GSK-3β) is highly desirable therapeutic target in cancer. Despite its involvement pathways associated with pathogenesis several malignancies, no selective GSK-3β inhibitor has been approved for treatment The regulatory role apoptosis, cycle, DNA repair, tumor growth, invasion, metastasis reflects relevance this provides rationale drug combinations. Emerging data on as mediator anticancer immune response also highlight potential clinical applications novel inhibitors that are entering studies. This manuscript reviews preclinical early results delineates developmental therapeutics landscape potentially important cancer therapy.

Language: Английский

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GSK3β as a novel promising target to overcome chemoresistance in pancreatic cancer

Drug Resistance Updates, Journal Year: 2021, Volume and Issue: 58, P. 100779 - 100779

Published: Aug. 12, 2021

Pancreatic cancer is an aggressive malignancy with increasing incidence and poor prognosis due to its late diagnosis intrinsic chemoresistance. Most pancreatic patients present locally advanced or metastatic disease characterized by inherent resistance chemotherapy. These features pose a series of therapeutic challenges new targets are urgently needed. Glycogen synthase kinase 3 beta (GSK3β) conserved serine/threonine kinase, which regulates key cellular processes including cell proliferation, DNA repair, cycle progression, signaling metabolic pathways. GSK3β implicated in non-malignant malignant diseases inflammation, neurodegenerative diseases, diabetes cancer. recently emerged among the factors involved onset progression cancer, as well acquisition Intensive research has been conducted on oncogenic functions potential druggable target; currently developed inhibitors display promising results preclinical models distinct tumor types, Here, we review latest findings about GSK-3β biology role development Moreover, discuss agents targeting that could be administered monotherapy combination other drugs surmount Several studies also defining gene signatures identify who might benefit from GSK3β-based intervention. This detailed overview emphasizes urgent need additional molecular impact inhibition structural analysis novel compounds omics predictive biomarkers.

Language: Английский

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Accelerated Bone Regeneration by Astragaloside IV through Stimulating the Coupling of Osteogenesis and Angiogenesis

International Journal of Biological Sciences, Journal Year: 2021, Volume and Issue: 17(7), P. 1821 - 1836

Published: Jan. 1, 2021

Both osteoblasts and preosteoclasts contribute to the coupling of osteogenesis angiogenesis, regulating bone regeneration. Astragaloside IV (AS-IV), a glycoside cycloartane-type triterpene derived from Chinese herb Astragalus membranaceus, exhibits various biological activities, including stimulating angiogenesis attenuating ischemic-hypoxic injury. However, effects underlying mechanisms AS-IV in osteogenesis, osteoclastogenesis, regeneration remain poorly understood. In present study, we found that treatment inhibited preserved preosteoclasts, enhanced platelet-derived growth factor-BB (PDGF-BB)-induced angiogenesis. Additionally, promoted cell viability, osteogenic differentiation, angiogenic gene expression marrow mesenchymal stem cells (BMSCs). The activation AKT/GSK-3β/β-catenin signaling was on osteoclastogenesis osteogenesis. Furthermore, accelerated during distraction (DO), as evidenced improved radiological histological manifestations biomechanical parameters, accompanied by within zone. summary, accelerates DO, enhancing preosteoclast-induced simultaneously, partially through signaling. These findings reveal may serve potential bioactive molecule for promoting imply be promising therapeutic target patients DO treatment.

Language: Английский

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Immunometabolism in cancer: basic mechanisms and new targeting strategy

Cell Death Discovery, Journal Year: 2024, Volume and Issue: 10(1)

Published: May 16, 2024

Abstract Maturing immunometabolic research empowers immune regulation novel approaches. Progressive metabolic adaptation of tumor cells permits a thriving microenvironment (TME) in which always lose the initial killing capacity, remains an unsolved dilemma even with development checkpoint therapies. In recent years, many studies on immunometabolism have been reported. The may facilitate anti-tumor immunotherapy from recurrent crosstalk between metabolism and immunity. Here, we discuss clinical core signaling pathways their inhibitors or agonists, as well specific functions these regulating immunity metabolism, some identified checkpoints. Understanding comprehensive advances helps to revise status quo cancer treatment.

Language: Английский

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Inhibition of GSK-3β activity suppresses HCC malignant phenotype by inhibiting glycolysis via activating AMPK/mTOR signaling

Cancer Letters, Journal Year: 2019, Volume and Issue: 463, P. 11 - 26

Published: Aug. 9, 2019

Language: Английский

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