Inhibition of NF-<i>κ</i>B by Dehydroxymethylepoxyquinomicin Suppresses Invasion and Synergistically Potentiates Temozolomide and <i>γ</i>-Radiation Cytotoxicity in Glioblastoma Cells

Brassesco, María Sol; Roberto, Gabriela Molinari; Morales, Andressa Gois; Oliveira, Jaqueline Carvalho de; Delsin, Lara Elis Alberici; Pezuk, Julia Alejandra; Valera, Elvis Terci; Carlotti, Carlos Gilberto; Rego, Eduardo Magalhães; Oliveira, Harley Francisco de; Scrideli, Carlos Alberto; Umezawa, Kazuo; Tone, Luíz Gonzaga

doi:10.1155/2013/593020

Cited by 27 publications

(23 citation statements)

References 63 publications

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“…Proneural-mesenchymal transition (PMT) has been identified as a process of cancer progression and is related to the mechanism for TMZ resistance in GBM [20]. The induction of PMT post-radiation therapy through the activation of the NF-κB and STAT3 pathways by inflammatory agents, such as IL-6, TNF-α, etc., has been found in GBM [32][33][34]. Moreover, IL-6 overexpression has been identified as a marker of malignancy in GBM [35].…”

Section: Discussionmentioning

confidence: 98%

“…The overexpression of ectopic p65 or high constitutive NF-κB activity has been shown to elevate MGMT and thereby enhance chemoresistance to alkylating agents in detected cells [37]. In contrast, the inhibition of NF-κB by the small molecule inhibitor BAY 11-7082 or by siRNA-mediated gene silencing reduced MGMT levels and thereby sensitized glioma stem-like cells to TMZ treatment [30,32]. Here, we found that H2AFJ expression causally modulates the activity of NF-κB in GBM cells.…”

Section: Discussionmentioning

confidence: 99%

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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: 98%

Section: Discussionmentioning

confidence: 99%

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

Lee

Lin

et al. 2019

Cancers

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“…Several therapeutic inhibitors which can block NF-κB activation are in development. Dehydroxymethylepoxyquinomicin (DHMEQ) has been reported to be an effective NF-κB inhibitor with antiproliferative properties in GBM (40). Triptolide was able to inhibit NF-κB signaling in glioma initiating cells, and then synergistically enhances TMZ-induced apoptosis (41).…”

Section: Discussionmentioning

confidence: 99%

Sulforaphane reverses chemo-resistance to temozolomide in glioblastoma cells by NF-κB-dependent pathway downregulating MGMT expression

Lan

Yang

Han

et al. 2015

International Journal of Oncology

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Abstract. The survival benefits of patients with glioblastoma (GBM) remain unsatisfactory due to the intrinsic or acquired resistance to temozolomide (TMZ). We elucidated the mechanisms of sulforaphane (SFN) reverse TMZ resistance in TMZ-inducing cell lines by inhibiting nuclear factor-κB (NF-κB) transcriptional activity. TMZ-resistant cell lines (U87-R and U373-R) were generated by stepwise (6 months) exposure of parental cells to TMZ. Luciferase reporter assay, biochemical assays and subcutaneous tumor establishment were used to characterize the antitumor effect of SFN. MGMT expression and 50% inhibiting concentration (IC 50 ) values of TMZ in GBM cell lines were assessed. Next, we established that U87-R and U373-R cells presenting high IC 50 of TMZ, activated NF-κB transcription and significantly increased MGMT expression compared with untreated cells. Furthermore, we revealed that SFN could significantly suppress proliferation of TMZ-resistant GBM cells. In addition, SFN effectively inhibited activity of NF-κB signaling pathway and then reduced MGMT expression to reverse the chemo-resistance to TMZ in T98G, U87-R and U373-R cell lines. Sequential combination with TMZ synergistically inhibited survival capability and increased the induction of apoptosis in TMZ-resistant GBM cells. Finally, a nude mouse model was established with U373-R cell subcutaneous tumor-bearing mice, and results showed that SFN could remarkably suppress cell growth and enhance cell death in chemo-resistant xenografts in the nude mouse model. Collectively, the present study suggests that the clinical efficacy of TMZ-based chemotherapy in TMZ-resistant GBM may be improved by combination with SFN.

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“…Preclinical testing of DHMEQ demonstrated inhibition of NF-κB activation and nuclear translocation, which led to decreased proliferation in GBM cells in vitro and decreased tumor growth in vivo . DHMEQ treatment also synergizes with TMZ and radiation, indicating strong therapeutic potential [69]. Recently, we published in vivo data demonstrating Withaferin A (WA), an IKKβ inhibitor, showed promise at inhibiting NF-κB and GBM growth [70].…”

Section: Nf-κb Signaling In Glioma: Preclinical Datamentioning

confidence: 99%

NF-κB and STAT3 in glioblastoma: therapeutic targets coming of age

Gray¹,

McFarland²,

Nozell³

et al. 2014

Expert Review of Neurotherapeutics

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Since we last addressed the roles of NF-κB and JAK/STAT3 signaling in glioblastoma (GBM) five years ago, tremendous strides have been made in the understanding of these two pathways in glioma biology. Contributing to prosurvival mechanisms, cancer stem cell maintenance, and treatment resistance, both NF-κB and STAT3 have been characterized as major drivers of GBM. In this review, we address general improvements in the molecular understanding of GBM, the structure of NF-κB and STAT3 signaling, the ways in which these pathways contribute to GBM, and advances in preclinical and clinical targeting of these two signaling cascades.

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Inhibition of NF-κB by Dehydroxymethylepoxyquinomicin Suppresses Invasion and Synergistically Potentiates Temozolomide and γ-Radiation Cytotoxicity in Glioblastoma Cells

Cited by 27 publications

References 63 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

Sulforaphane reverses chemo-resistance to temozolomide in glioblastoma cells by NF-κB-dependent pathway downregulating MGMT expression

NF-κB and STAT3 in glioblastoma: therapeutic targets coming of age

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