Glycogen synthase kinase-3β regulates astrocytic differentiation of U87-MG human glioblastoma cells

Li, Yan; Lu, Huimin; Li, Gang; Gao, Yan

doi:10.1038/aps.2010.10

Cited by 14 publications

(10 citation statements)

References 27 publications

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“…the reduction of SCs in solid tumors by treatment with agents that induce differentiation [ 55 ], has been proposed as a novel therapeutic approach. In GBM PTEN has been putatively identified to contribute to differentiation [ 56 , 42 ], however, in contrast to some recent publications [ 41 , 42 , 57 , 58 ], several of which focus on established cell lines [ 57 , 58 ], we find no evidence of PI3K signaling contributing to the differentiation from SC to DC, except in a trivial sense. Alterations in the number of DCs (defined morphologically and by GFAP expression) that can be induced from SCs in the presence of absence of PI-103 are most likely due to the sharp decrease in proliferation upon PI3K inhibition and not a direct effect of an altered differentiation potential.…”

Section: Discussioncontrasting

confidence: 99%

A Potential Role for the Inhibition of PI3K Signaling in Glioblastoma Therapy

et al. 2015

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Glioblastoma multiforme (GBM) is the most common primary brain tumor and among the most difficult to treat malignancies per se. In almost 90% of all GBM alterations in the PI3K/Akt/mTOR have been found, making this survival cascade a promising therapeutic target, particular for combination therapy that combines an apoptosis sensitizer, such as a pharmacological inhibitor of PI3K, with an apoptosis inducer, such as radio- or chemotherapy. However, while in vitro data focusing mainly on established cell lines has appeared rather promising, this has not translated well to a clinical setting. In this study, we analyze the effects of the dual kinase inhibitor PI-103, which blocks PI3K and mTOR activity, on three matched pairs of GBM stem cells/differentiated cells. While blocking PI3K-mediated signaling has a profound effect on cellular proliferation, in contrast to data presented on two GBM cell lines (A172 and U87) PI-103 actually counteracts the effect of chemotherapy. While we found no indications for a potential role of the PI3K signaling cascade in differentiation, we saw a clear and strong contribution to cellular motility and, by extension, invasion. While blocking PI3K-mediated signaling concurrently with application of chemotherapy does not appear to be a valid treatment option, pharmacological inhibitors, such as PI-103, nevertheless have an important place in future therapeutic approaches.

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Section: Discussioncontrasting

confidence: 99%

A Potential Role for the Inhibition of PI3K Signaling in Glioblastoma Therapy

et al. 2015

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“…The MTT results are in accordance with the enzyme assay results with IC50 37 μM and > 100 μM for compounds 102 and 4, respectively (Table 1). The results, confirm the importance of GSK-3β in cancer progression and open new avenues for the use of the synthon I derivatives GSK-3β inhibitors as anti-cancer drugs [18].…”

Section: Gsk-3β Inhibitors Activitysupporting

confidence: 70%

“…Next step was to determine if these compounds have any pharmacological activities as potential anticancer treatments. The U-87 glioma cell line was used in the MTT assay as it is known to express GSK-3β [18]. The most active (compound 102) and the least active (compound 4) compounds from the enzyme assay were chosen to assess their anti-proliferative activity.…”

Section: Gsk-3β Inhibitors Activitymentioning

confidence: 99%

Targeting GSK-3β enzyme by diazepino-quinolone derivatives

Swellmeen¹,

Basheer²,

Uzrail³

et al. 2022

Trop. J. Pharm Res

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Purpose: To synthesize a heterocyclic system containing quinolone and diazepine scaffolds as GSK-3β inhibitor. Methods: The diazepino-quinoline derivatives were synthesized starting from quinolone nucleus in a simple chemical reaction. The in vitro GSK-3β enzyme assay and MTT assay against cancer cell lines were carried out followed by Z´ı-LYTE GSK-3β assay. Anticancer activity was determined using U-87 glioma cell line. Results: Diazepino-quinoline derivatives were obtained in a good yield, and compound 102 exhibited significant activity against in vitro GSK-3β (IC50: 0.114 μM), and anticancer activity (IC50: 37 μM) against U-87 glioma cell line. Conclusion: The GSK-3β enzyme is a potential target to treat different diseases, and diazepines derivatives are a successful template for inhibitors design against GSK-3β enzyme with IC50 in a micromolar range.

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“…In this complex, Axin and APC function as scaffold proteins, and facilitate the phosphorylation of β‐catenin at the N‐terminus by GSK3β . Recent study showed that GSK3β activation induced differentiation and decreased proliferation of human GBM cells, while small interfering RNA against GSK3β suppressed the induced GBM cell differentiation . Our data indicates that GSK3β, as a negative regulator of Wnt/β‐catenin signaling pathway, may be downstream of Sohlh1.…”

Section: Discussionmentioning

confidence: 64%

Sohlh1 suppresses glioblastoma cell proliferation, migration, and invasion by inhibition of Wnt/β‐catenin signaling

Liu

Gao

Zhao

et al. 2018

Molecular Carcinogenesis

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Glioblastoma (GBM) is the most aggressive and highly invasive type of astrocytic tumors. Despite advances in diagnosis and therapy, the prognosis and survival time remain poor. Identifying key mediators of tumor cell proliferation, migration, and invasion is crucial to the development of new and more effective therapies. In this paper, we report the novel role of Spermatogenesis- and oogenesis- specific basic helix-loop-helix transcription factor1 (Sohlh1) in the inhibition of Wnt/β-catenin signaling and aggressive behaviors in GBM cells. Immunohistochemistry was performed to examine the expression of Sohlh1 and related proteins in astrocytomas. Human glioblastoma U87 and U251 cellswere transfected with appropriate plasmids and/or siRNAs to evaluate their functions on cell proliferation, migration, and invasion. Western blot and TOPflash luciferase assay were used to determine the involvement of Wnt/β-catenin signaling pathway in Sohlh1-mediated cellular activities in glioblastomas. We observed that Sohlh1 was downregulated in astrocytomas. The reduction in Sohlh1 expression was inversely correlated with the degree of malignancy in astrocytomas. In GBM cell lines, cellular proliferation, migration, and invasion were significantly enhanced after Sohlh1 knockdown, but significantly inhibited after Sohlh1 overexpression. These functional effects of Sohlh1 were achieved by upregulating GSK3β and inhibiting Wnt/β-catenin signaling. Our findings provide novel mechanistic insights of Sohlh1 in malignant progression of astrocytomas, suggesting that the level of Sohlh1 expression may be a predictor of astrocytoma behavior and further, Sohlh1 may serve as a potential therapeutic target for GBM.

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Glycogen synthase kinase-3β regulates astrocytic differentiation of U87-MG human glioblastoma cells

Cited by 14 publications

References 27 publications

A Potential Role for the Inhibition of PI3K Signaling in Glioblastoma Therapy

A Potential Role for the Inhibition of PI3K Signaling in Glioblastoma Therapy

Targeting GSK-3β enzyme by diazepino-quinolone derivatives

Sohlh1 suppresses glioblastoma cell proliferation, migration, and invasion by inhibition of Wnt/β‐catenin signaling

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