The CHAC1-inhibited Notch3 pathway is involved in temozolomide-induced glioma cytotoxicity

Chen, Peng Hsu; Shen, Wan Lin; Shih, Chwen‐Ming; Ho, Kuo Hao; Cheng, Chia‐Hsiung; Lin, Chun-Yu; Lee, Chin-Cheng; Liu, Ann Jeng; Chen, Ku‐Chung

doi:10.1016/j.neuropharm.2016.12.011

Cited by 45 publications

(47 citation statements)

References 32 publications

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“…It has been reported that JNK1 affects chemosensitivity of colon cancer cells by regulating autophagy . In glioma cells, JNK1/c‐JUN signalling pathway enhances the transcription of CHAC1 which induces cell death and serves as a target of TMZ . Conformed to a DNA microarray data, our study also suggested that MAPK8 was a protective factor for GBM patients' survival.…”

Section: Discussionsupporting

confidence: 64%

A risk signature with four autophagy‐related genes for predicting survival of glioblastoma multiforme

Wang

Zhao

Xiao

et al. 2020

J Cellular Molecular Medi

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Glioblastoma multiforme (GBM) is a devastating brain tumour without effective treatment. Recent studies have shown that autophagy is a promising therapeutic strategy for GBM. Therefore, it is necessary to identify novel biomarkers associated with autophagy in GBM. In this study, we downloaded autophagy-related genes from Human Autophagy Database (HADb) and Gene Set Enrichment Analysis (GSEA) website. Least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression analysis were performed to identify genes for constructing a risk signature. A nomogram was developed by integrating the risk signature with clinicopathological factors. Time-dependent receiver operating characteristic (ROC) curve and calibration plot were used to evaluate the efficiency of the prognostic model. Finally, four autophagy-related genes (DIRAS3, LGALS8, MAPK8 and STAM)were identified and were used for constructing a risk signature, which proved to be an independent risk factor for GBM patients. Furthermore, a nomogram was developed based on the risk signature and clinicopathological factors (IDH1 status, age and history of radiotherapy or chemotherapy). ROC curve and calibration plot suggested the nomogram could accurately predict 1-, 3-and 5-year survival rate of GBM patients.For function analysis, the risk signature was associated with apoptosis, necrosis, immunity, inflammation response and MAPK signalling pathway. In conclusion, the risk signature with 4 autophagy-related genes could serve as an independent prognostic factor for GBM patients. Moreover, we developed a nomogram based on the risk signature and clinical traits which was validated to perform better for predicting 1-, 3-and 5-year survival rate of GBM. K E Y W O R D Sautophagy, glioblastoma multiform, nomogram, prognosis, risk signature

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Section: Discussionsupporting

confidence: 64%

A risk signature with four autophagy‐related genes for predicting survival of glioblastoma multiforme

Wang

Zhao

Xiao

et al. 2020

J Cellular Molecular Medi

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“…This was also seen in a combination of Resveratrol and TMZ [13]. A recent report has shown TMZ reduced Notch 3 expression and activation in glioma [43]. In our study in TMZ group, GFAP increased and Notch4 decreased.…”

Section: Differentiationsupporting

confidence: 84%

Electromagnetic Field and Temozolomide Increase Differentiation of Human Glioblastoma Cell Line; concise view of mechanism

Ahmadi-Zeidabadi

Akbarnejad

Esmaeeli

et al. 2018

Preprint

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Glioblastoma is a highly malignant brain tumor with an extremely dismal prognosis, with a median survival of 12 months. Promoting glioma stem cell (GSC) differentiation is a crucial therapeutic strategy in treating glioblastoma to improve survival. We combine standard chemotherapy drug Temozolomide (TMZ) with Electromagnetic Field to evaluate their differentiation effects on glioma U87 cell line. Human glioma U87 cells exposed to electromagnetic field (EMF), Temozolomide (TMZ) alone and a combination of both were compared to control group. Nestin and CD133 were detected to identify stem-like cells (SLCs) changes during the experiment. The differentiation was found through detecting the expression of the glial fibrillary acidic protein (GFAP), and Notch4. We evaluated Ca + , SOD, and Notch as important chemical mediators in signal transduction to elucidate the mechanism of actions in the processes of differentiation. The expression of cancer SLC markers CD133, and neural stem/progenitor Nestin decreased in EMF/ Drug combined group compared to control which shows depletion of stem-like cell pool. In contrast, the differentiation of SLCs was increased by detecting the expression of the glial fibrillary acidic protein (GFAP), but, Notch4 decreased in Electromagnetic field/Drug combined group compared to control which shows a benign process of treatment. The differentiation was also confirmed by light microscopy. Morphological changes such as an elongated shape with elongated neurites, intercellular connection, and neurite branching were observed. Superoxide dismutase (SOD), Ca + and Notch were also increased as important chemical mediators in signal transduction. Here, we found the combination of pulsed electromagnetic fields (PEMFs) and TMZ significantly resulted in differentiation and glioma stem cells (GSCs) pool reduction that could have a profound therapeutic implication.

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“…For RNA-seq data for the TMZ-sensitive LN229 cells ( Figure 5 ), when comparing combined TMZ + OKN to UT treatments ( Figure 5 A ), an interesting downregulated gene includes PODXL (a marker for gastric cancer [53] ), and interesting upregulated genes include TRIB3 (induces apoptosis and reverses resistance to chemotherapy in hepatic carcinoma cells [54] ) and CHAC1 (enhances glioma apoptosis [55] ). When comparing combined TMZ + OKN treatment to TMZ alone ( Figure 5 B ), interesting downregulated genes are IGR1 (associated with shorter disease-free survival in patients whose tumors are ER positive and HER2 positive [56] ; IGF1R signaling pathway is very relevant in drug resistance [57] ), XIST (increased level associated with shorter survival and poorer prognosis [58] ), and PRKDC (prognostic biomarker for chemoresistance in breast cancer patients [59] ).…”

Section: Discussionmentioning

confidence: 99%

OKN-007 Increases temozolomide (TMZ) Sensitivity and Suppresses TMZ-Resistant Glioblastoma (GBM) Tumor Growth

Towner

Smith

Saunders

et al. 2019

Translational Oncology

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Treatment of glioblastoma (GBM) remains a challenge using conventional chemotherapy, such as temozolomide (TMZ), and is often ineffective as a result of drug resistance. We have assessed a novel nitrone-based agent, OKN-007, and found it to be effective in decreasing tumor volumes and increasing survival in orthotopic GBM xenografts by decreasing cell proliferation and angiogenesis and increasing apoptosis. In this study, we assessed combining OKN-007 with TMZ in vivo in a human G55 GBM orthotopic xenograft model and in vitro in TMZ-resistant and TMZ-sensitive human GBM cell lines. For the in vivo studies, magnetic resonance imaging was used to assess tumor growth and vascular alterations. Percent animal survival was also determined. For the in vitro studies, cell growth, IC50 values, RNA-seq, RT-PCR, and ELISA were used to assess growth inhibition, possible mechanism-of actions (MOAs) associated with combined OKN-007 + TMZ versus TMZ alone, and gene and protein expression levels, respectively. Microarray analysis of OKN-007–treated rat F98 glioma tumors was also carried out to determine possible MOAs of OKN-007 in glioma-bearing animals either treated or not treated with OKN-007. OKN-007 seems to elicit its effect on GBM tumors via inhibition of tumorigenic TGF-β1, which affects the extracellular matrix. When combined with TMZ, OKN-007 significantly increases percent survival, decreases tumor volumes, and normalizes tumor blood vasculature in vivo compared to untreated tumors and seems to affect TMZ-resistant GBM cells possibly via IDO-1, SUMO2, and PFN1 in vitro. Combined OKN-007 + TMZ may be a potentially potent treatment strategy for GBM patients.

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The CHAC1-inhibited Notch3 pathway is involved in temozolomide-induced glioma cytotoxicity

Cited by 45 publications

References 32 publications

A risk signature with four autophagy‐related genes for predicting survival of glioblastoma multiforme

A risk signature with four autophagy‐related genes for predicting survival of glioblastoma multiforme

Electromagnetic Field and Temozolomide Increase Differentiation of Human Glioblastoma Cell Line; concise view of mechanism

OKN-007 Increases temozolomide (TMZ) Sensitivity and Suppresses TMZ-Resistant Glioblastoma (GBM) Tumor Growth

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