The Role of GSK-3 in Cancer Immunotherapy: GSK-3 Inhibitors as a New Frontier in Cancer Treatment

Augello, Giuseppa; Emma, Maria Rita; Cusimano, Antonella; Azzolina, Antonina; Montalto, Giuseppe; McCubrey, James A.; Cervello, Melchiorre

doi:10.3390/cells9061427

Cited by 56 publications

(69 citation statements)

References 102 publications

(111 reference statements)

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“…We and others have found that natural compounds and their derivatives are potential drugs to kill cancer stem cells through GSK3β inhibition [ 67 , 68 ]. It is important to note that GSK3 inhibitors represent also interesting therapeutic tools to restore normal niche functions [ 69 ]. Thus, targeting both stem cells and their niche is crucial to restore physiological tissue regeneration ( Figure 6 ).…”

Section: Gsk3β As a Target For Precision Medicinementioning

confidence: 99%

GSK3β, a Master Kinase in the Regulation of Adult Stem Cell Behavior

Racaud‐Sultan

Vergnolle

2021

Cells

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In adult stem cells, Glycogen Synthase Kinase 3β (GSK3β) is at the crossroad of signaling pathways controlling survival, proliferation, adhesion and differentiation. The microenvironment plays a key role in the regulation of these cell functions and we have demonstrated that the GSK3β activity is strongly dependent on the engagement of integrins and protease-activated receptors (PARs). Downstream of the integrin α5β1 or PAR2 activation, a molecular complex is organized around the scaffolding proteins RACK1 and β-arrestin-2 respectively, containing the phosphatase PP2A responsible for GSK3β activation. As a consequence, a quiescent stem cell phenotype is established with high capacities to face apoptotic and metabolic stresses. A protective role of GSK3β has been found for hematopoietic and intestinal stem cells. Latters survived to de-adhesion through PAR2 activation, whereas formers were protected from cytotoxicity through α5β1 engagement. However, a prolonged activation of GSK3β promoted a defect in epithelial regeneration and a resistance to chemotherapy of leukemic cells, paving the way to chronic inflammatory diseases and to cancer resurgence, respectively. In both cases, a sexual dimorphism was measured in GSK3β-dependent cellular functions. GSK3β activity is a key marker for inflammatory and cancer diseases allowing adjusted therapy to sex, age and metabolic status of patients.

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Section: Gsk3β As a Target For Precision Medicinementioning

confidence: 99%

GSK3β, a Master Kinase in the Regulation of Adult Stem Cell Behavior

Racaud‐Sultan

Vergnolle

2021

Cells

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“…Feeder cells expressing HLA-E have been used to enrich for NKG2C + adaptive NK cells [ 98 ] yet it is unclear if the NKG2C + NK cells are significantly expanding or rather it is the lack of NKG2A + NK cells expanding due to inhibition through HLA-E. Another method to enhance expansion of adaptive NK cells involves the addition of the GSK3 inhibitor CHIR99021 to a feeder-free, IL-15 culture protocol [ 101 ]. GSK3 is a constitutively active serine-threonine kinase originally identified for its role in glucose metabolism, however has since been recognized in cell differentiation, survival and immune responses [ 102 ]. How GSK3 inhibition promotes the expansion of adaptive NK cells is unclear.…”

Section: Current Status On the Role Of Adaptive Nk Cells In Cancermentioning

confidence: 99%

Deciphering the Immunological Phenomenon of Adaptive Natural Killer (NK) Cells and Cytomegalovirus (CMV)

Barnes

Schilizzi

Audsley

et al. 2020

IJMS

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Natural killer (NK) cells play a significant and vital role in the first line of defense against infection through their ability to target cells without prior sensitization. They also contribute significantly to the activation and recruitment of both innate and adaptive immune cells through the production of a range of cytokines and chemokines. In the context of cytomegalovirus (CMV) infection, NK cells and CMV have co-evolved side by side to employ several mechanisms to evade one another. However, during this co-evolution the discovery of a subset of long-lived NK cells with enhanced effector potential, increased antibody-dependent responses and the potential to mediate immune memory has revolutionized the field of NK cell biology. The ability of a virus to imprint on the NK cell receptor repertoire resulting in the expansion of diverse, highly functional NK cells to this day remains a significant immunological phenomenon that only occurs in the context of CMV. Here we review our current understanding of the development of these NK cells, commonly referred to as adaptive NK cells and their current role in transplantation, infection, vaccination and cancer immunotherapy to decipher the complex role of CMV in dictating NK cell functional fate.

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“…After understanding their intracellular interactions, GSK3 inhibitors have been researched in the treatment of cancer ( 34 ). Many types of drugs have been developed ( 35 ) and are being tested in pre-clinical and phase I studies, with promising results ( 36 ).…”

Section: Discussionmentioning

confidence: 99%

Glycogen Synthase Kinase-3 Beta Expression Correlates With Worse Overall Survival in Non-Small Cell Lung Cancer—A Clinicopathological Series

Alves

Borges²,

Kimberly

et al. 2021

Front. Oncol.

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BackgroundGlycogen Synthase Kinase-3 beta (GSK-3β) regulates diverse cell functions including metabolic activity, signaling and structural proteins. GSK-3β phosphorylates target pro-oncogenes and regulates programmed cell death-ligand 1 (PD-L1). This study investigated the correlation between GSK-3β expression and clinically relevant molecular features of lung adenocarcinoma (PDL1 score, PTEN expression and driver mutations).MethodsWe evaluated 95 lung cancer specimens from biopsies and surgical resections. Immunohistochemistry was performed to analyze the expression of GSK-3β, PTEN, and PDL1. Epidemiological data, molecular characteristics and staging were evaluated from medical records. The histologic classification was performed by an experienced pulmonary pathologist.ResultsMost patients were female (52.6%) and the majority had a positive smoking history. The median age was 68.3 years, with individuals over 60 years accounting for 82.1%. The predominant histological subtype was adenocarcinoma (69.5%), followed by squamous cell carcinoma (20.0%). GSK-3β expression in tumors was cytoplasmic with a dotted pattern and perinuclear concentration, with associated membranous staining. Seven (7.3%) tumors had associated nuclear expression localization. Seventy-seven patients (81.1%) had advanced clinical-stage tumors. GSK-3β was positive in 75 tumors (78%) and GSK3-positive tumors tended to be diagnosed at advanced stages. Among stage III/IV tumors, 84% showed GSK3 positivity (p= 0.007). We identified a statistically significant association between GSK-3β and PTEN in the qualitative analysis (p 0.021); and when comparing PTEN to GSK-3β intensity 2+ (p 0.001) or 3+ expression (> 50%) – p 0.013. GSK-3β positive tumors with a high histological score had a worse overall survival.ConclusionWe identified the histological patterns of GSK-3β expression and evaluated its potential as marker for overall survival, establishing a simple histological score to measure the evaluated status in resected tissues. The use of GSK-3β expression as an immune response biomarker remains a challenge. Future studies will seek to explain the role of its interaction with PTEN.

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The Role of GSK-3 in Cancer Immunotherapy: GSK-3 Inhibitors as a New Frontier in Cancer Treatment

Cited by 56 publications

References 102 publications

GSK3β, a Master Kinase in the Regulation of Adult Stem Cell Behavior

GSK3β, a Master Kinase in the Regulation of Adult Stem Cell Behavior

Deciphering the Immunological Phenomenon of Adaptive Natural Killer (NK) Cells and Cytomegalovirus (CMV)

Glycogen Synthase Kinase-3 Beta Expression Correlates With Worse Overall Survival in Non-Small Cell Lung Cancer—A Clinicopathological Series

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