Wnt/β‐catenin signaling cascade: A promising target for glioma therapy

He, Lu; Zhou, Hong; Zeng, Zhiqing; Yao, Hailun; Jiang, Weiping; Qu, Hongtao

doi:10.1002/jcp.27186

Cited by 94 publications

(65 citation statements)

References 104 publications

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“…Importantly, it is involved in self-renewal of healthy stem cells (Majidinia, Aghazadeh, Jahanban-Esfahlani, & Yousefi, 2018;Uribe-Etxebarria, Agliano, Unda, & Ibarretxe, 2019) as well as of both solid cancer (Najafi, Farhood, & Mortezaee, 2019) and leukemia stem cells (LSCs) (Lento, Congdon, Voermans, Kritzik, & Reya, 2013). An aberrant increase in the levels of β-catenin exerts oncogenic effects via the activation of downstream gene expression programs in colorectal cancer (Morin et al, 1997;Rahmani, Avan, Hashemy, & Hassanian, 2018;Vermeulen et al, 2010), endometrial cancer (Giannakis et al, 2014;Liu, Chang, Lu, & Xiang, 2019), breast cancer (Gao et al, 2019;Khramtsov et al, 2010;Mohammadi-Yeganeh, Hosseini, & Paryan, 2019;Rahmani et al, 2019), prostate cancer (Pashirzad et al, 2019), bladder cancer (Xie et al, 2019), lung cancer (Wang, Zhou, Xu, & Hu, 2018b), glioblastoma (He et al, 2019) as well as in blood malignancies (Staal & Sen, 2008;Zhao et al, 2007). More specifically, ≥85% of pediatric T-ALL patients display increased β-catenin expression and upregulation of the Wnt target genes AXIN2, C-MYC, TCFL, and LEF (Arensman et al, 2014;Fernandes et al, 2017;Ng et al, 2014).…”

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confidence: 99%

Targeting Wnt/β‐catenin and PI3K/Akt/mTOR pathways in T‐cell acute lymphoblastic leukemia

Evangelisti

Chiarini

Cappellini

et al. 2020

Journal Cellular Physiology

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T‐cell acute lymphoblastic leukemia (T‐ALL) is an aggressive hematological disorder that results from the clonal transformation of T‐cell precursors. Phosphatidylinositol 3‐kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) and canonical Wnt/β‐catenin signaling pathways play a crucial role in T‐cell development and in self‐renewal of healthy and leukemic stem cells. Notably, β‐catenin is a transcriptional regulator of several genes involved in cancer cell proliferation and survival. In this way, aberrations of components belonging to the aforementioned networks contribute to T‐ALL pathogenesis. For this reason, inhibition of both pathways could represent an innovative strategy in this hematological malignancy. Here, we show that combined targeting of Wnt/β‐catenin pathway through ICG‐001, a CBP/β‐catenin transcription inhibitor, and of the PI3K/Akt/mTOR axis through ZSTK‐474, a PI3K inhibitor, downregulated proliferation, survival, and clonogenic activity of T‐ALL cells. ICG‐001 and ZSTK‐474 displayed cytotoxic effects, and, when combined together, induced a significant increase in apoptotic cells. This induction of apoptosis was associated with the downregulation of Wnt/β‐catenin and PI3K/Akt/mTOR pathways. All these findings were confirmed under hypoxic conditions that mimic the bone marrow niche where leukemic stem cells are believed to reside. Taken together, our findings highlight potentially promising treatment consisting of cotargeting Wnt/β‐catenin and PI3K/Akt/mTOR pathways in T‐ALL settings.

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confidence: 99%

Targeting Wnt/β‐catenin and PI3K/Akt/mTOR pathways in T‐cell acute lymphoblastic leukemia

Evangelisti

Chiarini

Cappellini

et al. 2020

Journal Cellular Physiology

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“…. The efficacy of aspirin has been demonstrated in several types of solid tumors, but its effects in brain-derived cancers have been poorly investigated, although the drug was shown to have, for instance, an antitumor action in glioblastoma cells via the activation of apoptosis cascade and the modulation of β-catenin/T-cell factor-mediated transcription activity(He et al, 2018;Lan et al, 2011).GBM is one of the most aggressive human cancers and the deadliest primary brain tumor. GBM's highly heterogeneous nature F I G U R E 2 Concentration dependence of the effects of aspirin on GBM CSCs growth.…”

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confidence: 99%

Aspirin inhibits cancer stem cells properties and growth of glioblastoma multiforme through Rb1 pathway modulation

Pozzoli

Marei

Althani

et al. 2019

Journal Cellular Physiology

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Several clinical studies indicated that the daily use of aspirin or acetylsalicylic acid reduces the cancer risk via cyclooxygenases (Cox‐1 and Cox‐2) inhibition. In addition, aspirin‐induced Cox‐dependent and ‐independent antitumor effects have also been described. Here we report, for the first time, that aspirin treatment of human glioblastoma cancer (GBM) stem cells, a small population responsible for tumor progression and recurrence, is associated with reduced cell proliferation and motility. Aspirin did not interfere with cell viability but induced cell‐cycle arrest. Exogenous prostaglandin E2 significantly increased cell proliferation but did not abrogate the aspirin‐mediated growth inhibition, suggesting a Cox‐independent mechanism. These effects appear to be mediated by the increase of p21 waf1 and p27 Kip1, associated with a reduction of Cyclin D1 and Rb1 protein phosphorylation, and involve the downregulation of key molecules responsible for tumor development, that is, Notch1, Sox2, Stat3, and Survivin. Our results support a possible role of aspirin as adjunctive therapy in the clinical management of GBM patients.

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“…In addition, TRIM24 has been suggested to promote cancer progression by triggering the Wnt/β-catenin signaling pathway [21,22]. This pathway has been noted to be closely associated with cellular proliferation, migration, and angiogenesis and the following glioma malignancy [23]. We assumed that NCK1-AS1 could affect glioma progression through the miR-138-2-3p/TRIM24 network and the following Wnt/β-catenin pathway, with gain-and loss-of functions of these molecules performed in both cell and animal experiments to validate this hypothesis.…”

Section: Introductionmentioning

confidence: 99%

Long non-coding RNA NCK1-AS1 promotes the tumorigenesis of glioma through sponging microRNA-138-2-3p and activating the TRIM24/Wnt/β-catenin axis

Huang

et al. 2020

J Exp Clin Cancer Res

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Background: Glioma is a common brain malignancy with high mortality. The competing endogenous RNA (ceRNA) networks may play key roles in cancer progression. This study was conducted to probe the role of long noncoding RNA (lncRNA) NCK1-AS1 in glioma progression and the involved mechanisms.Methods: Microarray analyses were performed to explore the lncRNAs/miRNAs/genes with differential expression in glioma. NCK1-AS1 levels in glioma tissues and normal brain tissues, and in glioma cell lines and normal human glial cells were identified. The interactions among NCK1-AS1, miR-138-2-3p and TRIM24 were validated through luciferase reporter, RNA immunoprecipitation and RNA pull-down assays. Gain-and loss-of functions of NCK1-AS1, miR-138-2-3p and TRIM24 were performed to identify their roles in the behaviors of glioma cells. The activity of the Wnt/β-catenin pathway was measured. In vivo experiments were performed as well.Results: High expression of NCK1-AS1 was found in glioma tissues and cells, especially in U251 cells. Online predictions and the integrated experiments identified that NCK1-AS1 elevated the TRIM24 expression through sponging miR-138-2-3p, and further activated the Wnt/β-catenin pathway. Artificial silencing of NCK1-AS1 or upregulation of miR-138-2-3p led to inhibited proliferation, invasion and migration but promoted cell apoptosis of U251 cells, while up-regulation of TRIM24 reversed these changes, and it activated the Wnt/β-catenin pathway. The in vitro results were reproduced in in vivo experiments.Conclusions: Our study suggested that NCK1-AS1 might elevate TRIM24 expression and further activate the Wnt/βcatenin pathway via acting as a ceRNA for miR-138-2-3p. Silencing of NCK1-AS1 might inhibit the progression of glioma.

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Wnt/β‐catenin signaling cascade: A promising target for glioma therapy

Cited by 94 publications

References 104 publications

Targeting Wnt/β‐catenin and PI3K/Akt/mTOR pathways in T‐cell acute lymphoblastic leukemia

Targeting Wnt/β‐catenin and PI3K/Akt/mTOR pathways in T‐cell acute lymphoblastic leukemia

Aspirin inhibits cancer stem cells properties and growth of glioblastoma multiforme through Rb1 pathway modulation

Long non-coding RNA NCK1-AS1 promotes the tumorigenesis of glioma through sponging microRNA-138-2-3p and activating the TRIM24/Wnt/β-catenin axis

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