Aberrantly activated Cox-2 and Wnt signaling interact to maintain cancer stem cells in glioblastoma

Wu, Megan; Guan, Jennifer; Li, Chris; Gunter, Simon J; Nusrat, Labeeba; Ng, S. C.; Dhand, Karan; Morshead, Cindi M.; Kim, Albert; Das, Sunit

doi:10.18632/oncotarget.19283

Cited by 34 publications

(46 citation statements)

References 52 publications

(54 reference statements)

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“…Микроокружение опухоли играет важную роль в канцерогенезе глиобластомы, влияя на фенотип СКГ. Было показано, что COX2 (циклооксигеназа 2) ассоциированный сигнальный путь и повышенный синтез PGE2 (простагландин E2) приводят к увеличению пролиферации и самообновления СКГ и НСК in vitro посредством активации Wnt / β-катенин-каскада, в то время как ингибирование COX2 индуцировало дифференцировку и потерю фенотипа СКГ [61].…”

Section: обзорные статьиunclassified

Wnt-signaling pathway in pathogenesis of glioblastoma multiforme

et al. 2019

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The Wnt-signaling pathway regulates various biological processes, such as embryonic development, self-renewal, proliferation, differentiation and migration of stem cells. The Wnt-signaling is involved in tumor progression by aberrant activation in stem-like cells, called cancer stem cells, in different kinds of tumor, including multiform glioblastoma. The Wnt-signaling promotes stemness, invasion, metastasis, therapeutic and immune resistance of cancer stem cells in multiform glioblastoma. To summarize, targeting the Wnt-signaling pathway as an oncogenic driver is the future hope for effective therapy of glioblastoma for which current standard therapy is not effective.In this review, we focused on functions of the Wnt-signaling in cancer stem cells and involvement of the Wnt-signaling pathway in gliomagenesis.

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Section: обзорные статьиunclassified

Wnt-signaling pathway in pathogenesis of glioblastoma multiforme

et al. 2019

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“…Increasing levels of COX-2 expression and prostaglandin E2 are associated with cell proliferation, invasion, and angiogenesis, and apoptosis inhibition, and the COX-2 expression level is positively correlated with glioma grade [177]. Furthermore, an aberrant positive feedback interaction between the COX-2/PGE2 and WNT pathways stimulates the self-renewal and proliferation of GSCs [178]. WNT signaling underlies GSC identity directly through COXindependent WNT signaling, and indirectly through COX/ PGE2-dependent WNT signaling [178].…”

Section: Interactions Between B-catenin Signaling and Ppar-c Agonistsmentioning

confidence: 99%

“…Furthermore, an aberrant positive feedback interaction between the COX-2/PGE2 and WNT pathways stimulates the self-renewal and proliferation of GSCs [178]. WNT signaling underlies GSC identity directly through COXindependent WNT signaling, and indirectly through COX/ PGE2-dependent WNT signaling [178].…”

Section: Interactions Between B-catenin Signaling and Ppar-c Agonistsmentioning

confidence: 99%

“…However, the association of TMZ with LY294002, a PI3K inhibitor, decreases GSC proliferation and invasion [222,226]. The cytotoxicity of TMZ induced by inhibition of PGE2 affords only a modest survival advantage and fails to prevent glioma progression because of COX-independent WNT activation [178]. Resistance to TMZ may be explained by targeting downstream targets of the WNT/b-catenin pathway, and the combination of inhibitors of WNT and/or PI3K, such as PPAR-c agonists, with TMZ may enhance its effects (Fig.…”

Section: Temozolomide In Gliomasmentioning

confidence: 99%

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Opposite Interplay Between the Canonical WNT/β-Catenin Pathway and PPAR Gamma: A Potential Therapeutic Target in Gliomas

Vallée

Lecarpentier²,

Guillevin

et al. 2018

Neurosci. Bull.

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In gliomas, the canonical Wingless/Int (WNT)/β-catenin pathway is increased while peroxisome proliferator-activated receptor gamma (PPAR-γ) is downregulated. The two systems act in an opposite manner. This review focuses on the interplay between WNT/β-catenin signaling and PPAR-γ and their metabolic implications as potential therapeutic target in gliomas. Activation of the WNT/β-catenin pathway stimulates the transcription of genes involved in proliferation, invasion, nucleotide synthesis, tumor growth, and angiogenesis. Activation of PPAR-γ agonists inhibits various signaling pathways such as the JAK/STAT, WNT/β-catenin, and PI3K/Akt pathways, which reduces tumor growth, cell proliferation, cell invasiveness, and angiogenesis. Nonsteroidal anti-inflammatory drugs, curcumin, antipsychotic drugs, adiponectin, and sulforaphane downregulate the WNT/β-catenin pathway through the upregulation of PPAR-γ and thus appear to provide an interesting therapeutic approach for gliomas. Temozolomide (TMZ) is an antiangiogenic agent. The downstream action of this opposite interplay may explain the TMZ-resistance often reported in gliomas.

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“…The enhanced expression of COX-2 protein has been correlated with many aggressive aspects of the disease, such as rate of GBM cell proliferation [13], histopathological grade of glioma [14,15], and poor prognosis and survival [16][17][18][19]. Furthermore, evidence has been reported that the COX-2 pathway, through the stimulation of the GSC self-renewal and proliferation, could contribute to chemo-and radioresistance [20][21][22]. Hence, COX-2 has been proposed as a strong predictor of poor survival and aggressiveness [12,18] as well as its targeting with specific COX-2 inhibitors is emerging as a potential anti-glioma strategy [12,14,23,24].…”

Section: Introductionmentioning

confidence: 99%

Biological effects of selective COX-2 inhibitor NS398 on human glioblastoma cell lines

et al. 2020

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Background: Cyclooxygenase-2 (COX-2), an inflammation-associated enzyme, has been implicated in tumorigenesis and progression of glioblastoma (GBM). The poor survival of GBM was mainly associated with the presence of glioma stem cells (GSC) and the markedly inflammatory microenvironment. To further explore the involvement of COX-2 in glioma biology, the effects of NS398, a selective COX-2 inhibitor, were evaluated on GSC derived from COX-2 expressing GBM cell lines, i.e., U87MG and T98G, in terms of neurospheres' growth, autophagy, and extracellular vesicle (EV) release. Methods: Neurospheres' growth and morphology were evaluated by optical and scanning electron microscopy. Autophagy was measured by staining acidic vesicular organelles. Extracellular vesicles (EV), released from neurospheres, were analyzed by transmission electron microscopy. The autophagic proteins Beclin-1 and LC3B, as well as the EV markers CD63 and CD81, were analyzed by western blotting. The scratch assay test was used to evaluate the NS398 influence on GBM cell migration. Results: Both cell lines were strongly influenced by NS398 exposure, as showed by morphological changes, reduced growth rate, and appearance of autophagy. Furthermore, the inhibitor led to a functional change of EV released by neurospheres. Indeed, EV secreted by NS398-treated GSC, but not those from control cells, were able to significantly inhibit adherent U87MG and T98G cell migration and induced autophagy in recipient cells, thus leading to effects quite similar to those directly caused by NS398 in the same cells. Conclusion: Despite the intrinsic diversity and individual genetic features of U87MG and T98G, comparable effects were exerted by the COX-2 inhibitor NS398 on both GBM cell lines. Overall, our findings support the crucial role of the inflammatory-associated COX-2/PGE2 system in glioma and glioma stem cell biology.

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Aberrantly activated Cox-2 and Wnt signaling interact to maintain cancer stem cells in glioblastoma

Cited by 34 publications

References 52 publications

Wnt-signaling pathway in pathogenesis of glioblastoma multiforme

Wnt-signaling pathway in pathogenesis of glioblastoma multiforme

Opposite Interplay Between the Canonical WNT/β-Catenin Pathway and PPAR Gamma: A Potential Therapeutic Target in Gliomas

Biological effects of selective COX-2 inhibitor NS398 on human glioblastoma cell lines

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