Inhibition of NF-κB results in anti-glioma activity and reduces temozolomide-induced chemoresistance by down-regulating MGMT gene expression

Yu, Zhiyun; Chen, Yong; Wang, Shiqiang; Li, Pengliang; Zhou, Guangtong; Yuan, Yongjie

doi:10.1016/j.canlet.2018.04.033

Cited by 55 publications

(37 citation statements)

References 29 publications

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“…Moreover, artificially silencing H2AFJ sensitized but overexpressing H2AFJ desensitized GBM cells to the cancericidal effect of TMZ. In GBM patients who lack methylation at the MGMT promoter region, a GBM subpopulation presumably insensitive to TMZ treatment [30,31], we found that H2AFJ upregulation is able to further differentiate a poorer TMZ-responsive subgroup from those patients. In addition, our data showed that H2AFJ upregulation is extensively detected in GBM tissues with wild-type IDH1, another indicator for a poor TMZ response [10,12].…”

Section: Discussionmentioning

confidence: 73%

Histone 2A Family Member J Drives Mesenchymal Transition and Temozolomide Resistance in Glioblastoma Multiforme

Lee

Lin

et al. 2019

Cancers

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Glioblastoma multiforme (GBM) is the most aggressive brain tumor and has a poor prognosis and is poorly sensitive to radiotherapy or temozolomide (TMZ) chemotherapy. Therefore, identifying new biomarkers to predict therapeutic responses of GBM is urgently needed. By using The Cancer Genome Atlas (TCGA) database, we found that the upregulation of histone 2A family member J (H2AFJ), but not other H2AFs, is extensively detected in the therapeutic-insensitive mesenchymal, IDH wildtype, MGMT unmethylated, or non-G-CIMP GBM and is associated with poor TMZ responsiveness independent of radiation. Similar views were also found in GBM cell lines. Whereas H2AFJ knockdown diminished TMZ resistance, H2AFJ overexpression promoted TMZ resistance in a panel of GBM cell lines. Gene set enrichment analysis (GSEA) revealed that H2AFJ upregulation accompanied by the activation of TNF-α/NF-κB and IL-6/STAT3-related pathways is highly predicted. Luciferase-based promoter activity assay further validated that the activities of NF-κB and STAT3 are causally affected by H2AFJ expression in GBM cells. Moreover, we found that therapeutic targeting HADC3 by tacedinaline or NF-κB by ML029 is likely able to overcome the TMZ resistance in GBM cells with H2AFJ upregulation. Significantly, the GBM cohorts harboring a high-level H2AFJ transcript combined with high-level expression of TNF-α/NF-κB geneset, IL-6/STAT3 geneset or HADC3 were associated with a shorter time to tumor repopulation after initial treatment with TMZ. These findings not only provide H2AFJ as a biomarker to predict TMZ therapeutic effectiveness but also suggest a new strategy to combat TMZ-insensitive GBM by targeting the interaction network constructed by TNF-α/NF-κB, IL-6/STAT3, HDAC3, and H2AFJ.

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Section: Discussionmentioning

confidence: 73%

Histone 2A Family Member J Drives Mesenchymal Transition and Temozolomide Resistance in Glioblastoma Multiforme

Lee

Lin

et al. 2019

Cancers

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“…To further examine the effect of 20(S)‐Rg3 synergistic activity with TMZ in vivo, U118 cells were injected into nude mice subcutaneously. According to some references, 23, 25 we selected 20 mg/kg 20(S)‐Rg3 and 20 mg/kg TMZ for the in vivo experiments. When the subcutaneous tumors reached a mean group size of around 100 mm 3 , mice were treated every day for 4 weeks with 20 mg/kg TMZ alone or 20 mg/kg 20(S)‐Rg3+ 20 mg/kg TMZ.…”

Section: Resultsmentioning

confidence: 99%

“…Because the drug concentration in the serum of mice with 40 mg/kg 20(S)‐Rg3 administered i.p. daily for 1 week reached a peak at approximately 200 μmol/L, and 30 mg/kg TMZ alone was unable to significantly inhibit glioma growth in vivo xenograft models, 20 mg/kg of 20(S)‐Rg3 and 20 mg/kg TMZ were selected for in vivo experiments. One of the groups received an i.p.…”

Section: Methodsmentioning

confidence: 99%

20(S)‐ginsenoside‐Rg3 reverses temozolomide resistance and restrains epithelial‐mesenchymal transition progression in glioblastoma

et al. 2018

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Glioblastoma multiforme (GBM) is one of the most malignant human intracranial tumors. Temozolomide (TMZ) is the primary alkylating agent for GBM patients. However, many GBM patients are resistant to TMZ. Therefore, patients with GBM urgently need more effective therapeutic options. 20(S)‐ginsenoside‐Rg3 (20(S)‐Rg3) is a natural chemical with anti‐tumor effects, but at present there is little understanding of its functional mechanism. Several research reports have demonstrated that O6‐methylguanine DNA‐methyltransferase (MGMT) repairs damaged DNA and contributes to TMZ resistance in gliomas. In addition, recent studies have shown that MGMT gene expression could be regulated by the Wnt/β‐catenin pathway. However, whether 20(S)‐Rg3 inhibits MGMT expression and augments chemosensitivity to Temozolomide (TMZ) in glioma cells remains unclear. In this study, we explored the modulating effects of 20(S)‐Rg3 on MGMT. We used glioma cell lines, primary cell strain (including T98G, U118 and GBM‐XX; all of them are MGMT‐positive glioma cell lines) and xenograft glioma models to examine whether 20(S)‐Rg3 increased the sensitivity to TMZ and to reveal the underlying mechanisms. We found that the MGMT expression was effectively downregulated by 20(S)‐Rg3 via the Wnt/β‐catenin pathway in glioma cell lines, and TMZ resistance was significantly reversed by 20(S)‐Rg3. Meanwhile, 20(S)‐Rg3 shows no obvious cytotoxicity at its effective dose and is well tolerated in vivo. In addition, we found that 20(S)‐Rg3 significantly restrains the epithelial‐mesenchymal transition (EMT) progression of glioma cells. Taken together, these results indicate that 20(S)‐Rg3 may be a novel agent to use in treatment of GBM, especially in TMZ‐resistant GBM with high MGMT expression.

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“…The induction of MGMT expression was related to TMZ insensitivity, and the decreased protein level of MGMT, as a favourable prognostic factor, was associated with better prognosis in patients with glioblastoma . Yu et al indicated that the expression of MGMT was regulated by NF‐κB activation. Previous studies demonstrated that the blockage of NF‐κB activation by specific NF‐κB inhibitors suppressed the expression of tumour progression‐associated proteins (XIAP, MMP‐2, MMP‐9, VEGF and Cyclin D1) and reduced cell invasion in glioblastoma .…”

Section: Discussionmentioning

confidence: 99%

“…Constitutive NF‐κB activation controls the expression of tumour progression‐associated proteins which participate in tumour cell growth, anti‐apoptosis, angiogenesis and metastasis . In addition, the expression of several DNA repair proteins is also linked to NF‐κB activation . Puliyappadamba et al demonstrated that glioblastoma had higher NF‐κB activation compared to normal brain and lower grade glioma …”

Section: Introductionmentioning

confidence: 99%

Induction of apoptosis through extrinsic/intrinsic pathways and suppression of ERK/NF‐κB signalling participate in anti‐glioblastoma of imipramine

Hsu

Chiang

Wang

2020

J Cellular Molecular Medi

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Glioblastomas are the most aggressive type of brain tumour, with poor prognosis even after standard treatment such as surgical resection, temozolomide and radiation therapy. The overexpression of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in glioblastomas is recognized as an important treatment target. Thus, an urgent need regarding glioblastomas is the development of a new, suitable agent that may show potential for the inhibition of extracellular signal-regulated kinase (ERK)/NF-κB-mediated glioblastoma progression. Imipramine, a tricyclic antidepressant, has anti-inflammatory actions against inflamed glial cells; additionally, imipramine can induce glioblastoma toxicity via the activation of autophagy. However, whether imipramine can suppress glioblastoma progression via the induction of apoptosis and blockage of ERK/NF-κB signalling remains unclear. The main purpose of this study was to investigate the effects of imipramine on apoptotic signalling and ERK/NF-κB-mediated glioblastoma progression by using cell proliferation (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide [MTT] assay), flow cytometry, Western blotting, and cell invasion/migration assay analysis in vitro. The ERK and NF-κB inhibitory capacity of imipramine is detected by NF-κB reporter gene assay and Western blotting. Additionally, a glioblastoma-bearing animal model was used to validate the therapeutic efficacy and general toxicity of imipramine. Our results demonstrated that imipramine successfully triggered apoptosis through extrinsic/intrinsic pathways and suppressed the invasion/migration ability of glioblastoma cells. Furthermore, imipramine effectively suppressed glioblastoma progression in vivo via the inhibition of the ERK/NF-κB pathway. In summary, imipramine is a potential anti-glioblastoma drug which induces apoptosis and has the capacity to inhibit ERK/NF-κB signalling. K E Y W O R D S ERK, extrinsic/intrinsic apoptosis, glioblastoma, imipramine, NF-κB | 3983 HSU et al.

show abstract

Inhibition of NF-κB results in anti-glioma activity and reduces temozolomide-induced chemoresistance by down-regulating MGMT gene expression

Cited by 55 publications

References 29 publications

Histone 2A Family Member J Drives Mesenchymal Transition and Temozolomide Resistance in Glioblastoma Multiforme

Histone 2A Family Member J Drives Mesenchymal Transition and Temozolomide Resistance in Glioblastoma Multiforme

20(S)‐ginsenoside‐Rg3 reverses temozolomide resistance and restrains epithelial‐mesenchymal transition progression in glioblastoma

Induction of apoptosis through extrinsic/intrinsic pathways and suppression of ERK/NF‐κB signalling participate in anti‐glioblastoma of imipramine

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