Temozolomide induces activation of Wnt/β-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy

Tomar, Vivek Singh; Patil, Vikas; Somasundaram, Kumaravel

doi:10.1007/s10565-019-09502-7

Cited by 58 publications

(43 citation statements)

References 19 publications

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“…Consistent with these findings, activation of the canonical Wnt/β-catenin signaling cascade induces MGMT expression, and its inhibition augments the cytotoxic effects of TMZ [44]. Recently, it was shown that Wnt pathway may contribute to TMZ resistance through induction of autophagy [45] and that Wnt activation upon TMZ treatment is mediated by PI3K/Akt pathway [46].…”

Section: Discussionmentioning

confidence: 57%

Revealing Temozolomide Resistance Mechanisms via Genome-Wide CRISPR Libraries

Rocha

Silva

et al. 2020

Cells

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Glioblastoma is a severe type of brain tumor with a poor prognosis and few therapy options. Temozolomide (TMZ) is one of these options, however, with limited success, and failure is mainly due to tumor resistance. In this work, genome-wide CRISPR-Cas9 lentiviral screen libraries for gene knockout or activation were transduced in the human glioblastoma cell line, aiming to identify genes that modulate TMZ resistance. The sgRNAs enriched in both libraries in surviving cells after TMZ treatment were identified by next-generation sequencing (NGS). Pathway analyses of gene candidates on knockout screening revealed several enriched pathways, including the mismatch repair and the Sonic Hedgehog pathways. Silencing three genes ranked on the top 10 list (MSH2, PTCH2, and CLCA2) confirm cell protection from TMZ-induced death. In addition, a CRISPR activation library revealed that NRF2 and Wnt pathways are involved in TMZ resistance. Consistently, overexpression of FZD6, CTNNB1, or NRF2 genes significantly increased cell survival upon TMZ treatment. Moreover, NRF2 and related genes detected in this screen presented a robust negative correlation with glioblastoma patient survival rates. Finally, several gene candidates from knockout or activation screening are targetable by inhibitors or small molecules, and some of them have already been used in the clinic.

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Section: Discussionmentioning

confidence: 57%

Revealing Temozolomide Resistance Mechanisms via Genome-Wide CRISPR Libraries

Rocha

Silva

et al. 2020

Cells

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“…RA inhibits the PI3K/Akt/NF-κB signaling pathway in glioma cells. PI3K/Akt/NF-κB signaling plays a vital role in cell proliferation, survival, and metabolism, and is constitutively activated in most tumors, including glioma (42)(43)(44). Therefore, the effect of RA on the PI3K/Akt/NF-κB signaling pathway was examined.…”

Section: Ra Increases Glioma Cell Apoptosis Apoptosis Plays a Crucial Role In Cancer Treatmentmentioning

confidence: 99%

Rosmarinic acid inhibits cell proliferation, migration, and invasion and induces apoptosis in human glioma cells

Liu

Tang

et al. 2021

Int J Mol Med

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There is a growing evidence that Fyn kinase is upregulated in glioblastoma multiforme (GBM), where it plays a key role in tumor proliferation and invasion. In the present study, the antitumor effects of rosmarinic acid (RA), a Fyn inhibitor, were explored in human-derived U251 and U343 glioma cell lines. These cells were treated with various concentrations of RA to determine its effects on proliferation, migration, invasion, apoptosis, and gene and protein expression levels. The CCK-8 assay revealed that RA significantly suppressed cell viability of U251 and U343 cells. Furthermore, RA significantly reduced proliferation rates, inhibited migration and invasion, and decreased the expression levels of invasion-related factors, such as matrix metalloproteinase (MMP)-2 and MMP-9. TUNEL staining revealed that RA resulted in a dose-dependent increase of U251 and U343 cell apoptosis. In line with this finding, the expression of apoptosis suppressor protein Bcl-2 was downregulated and that of the pro-apoptotic proteins Bax and cleaved caspase-3 was increased. In addition, it was revealed that the phosphatidylinositol 3-kinase (PI3K)/Akt/nuclear factor-κB (NF-κB) signaling pathway was involved in RA-induced cytotoxicity in U251 and U343 cells. Collectively, the present study suggested RA as a drug candidate for the treatment of GBM.

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“…Furthermore, Wnt/β-catenin signaling orchestrates multiple cell signaling cascades, such as epidermal growth factor receptor (EGFR), Hippo/YAP, nuclear factor kappa-B (NF-κB), Notch, Sonic Hedgehog and PI3K/Akt pathway, which contribute to pivotal molecular mechanism in cancer development [19][20][21][22][23][24]. EGFR could form a complex with β-catenin and promotes the invasion and metastasis of cancer cells [25,26].…”

Section: Introductionmentioning

confidence: 99%

“…Subsequently, stabilized β-catenin translocates into the nucleus and binds to TCF/LEF transcription factors to lead to target gene transcription. "WNT OFF state": In the absence of WNT ligand, the destruction complex of β-catenin, a tertiary complex formed by AXIN, CK1α, GSK3β and APC, phosphorylates β-catenin, which subsequently undergoes the ubiquitin-proteasomal degradation temozolomide [22]. Additionally, AKT kinase could also activate β-catenin.…”

Section: Introductionmentioning

confidence: 99%

Targeting the Wnt/β-catenin signaling pathway in cancer

2020

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The aberrant Wnt/β-catenin signaling pathway facilitates cancer stem cell renewal, cell proliferation and differentiation, thus exerting crucial roles in tumorigenesis and therapy response. Accumulated investigations highlight the therapeutic potential of agents targeting Wnt/β-catenin signaling in cancer. Wnt ligand/ receptor interface, β-catenin destruction complex and TCF/β-catenin transcription complex are key components of the cascade and have been targeted with interventions in preclinical and clinical evaluations. This scoping review aims at outlining the latest progress on the current approaches and perspectives of Wnt/β-catenin signaling pathway targeted therapy in various cancer types. Better understanding of the updates on the inhibitors, antagonists and activators of Wnt/β-catenin pathway rationalizes innovative strategies for personalized cancer treatment. Further investigations are warranted to confirm precise and secure targeted agents and achieve optimal use with clinical benefits in malignant diseases.

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Temozolomide induces activation of Wnt/β-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy

Cited by 58 publications

References 19 publications

Revealing Temozolomide Resistance Mechanisms via Genome-Wide CRISPR Libraries

Revealing Temozolomide Resistance Mechanisms via Genome-Wide CRISPR Libraries

Rosmarinic acid inhibits cell proliferation, migration, and invasion and induces apoptosis in human glioma cells

Targeting the Wnt/β-catenin signaling pathway in cancer

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