sincalide and Glioblastoma

The prognosis for the WHO grade 4 IDH-mutant astrocytoma is better than IDH-wildtype glioblastoma (GBM) patients. The purpose of this study is to explore the potential mechanism of how IDH1 mutation can increase the efficacy of radiotherapy and to establish a risk-score model to predict the efficacy of radiotherapy in WHO grade 4 gliomas. First, we conducted experimental study on the effect of IDH1

Topics: Brain Neoplasms; Calmodulin-Binding Proteins; Glioblastoma; Glioma; Humans; Isocitrate Dehydrogenase; Mutation; Prognosis; Sincalide; World Health Organization

Echinacoside (ECH) is a phenylethanoid extracted from the stems of Cistanches salsa, an herb used in Chinese medicine formulations, and is effective against glioblastoma multiforme (GBM). Epithelial-mesenchymal transition (EMT) is the cornerstone of tumorigenesis and metastasis, and increases the malignant behavior of GBM cells. The S phase kinase-related protein 2 (skp2), an oncoprotein associated with EMT, is highly expressed in GBM and significantly associated with drug resistance, tumor grade and dismal prognosis. The aim of this study was to explore the inhibitory effects of ECH against GBM development and skp2-induced EMT.. CCK-8, EdU incorporation, transwell, colony formation and sphere formation assays were used to determine the effects of ECH on GBM cell viability, proliferation, migration and invasion in vitro. The in vivo anti-glioma effects of ECH were examined using a U87 xenograft model. The expression levels of skp2 protein, EMT-associated markers (vimentin and snail) and stemness markers (Nestin and sox2) were analyzed by immunofluorescence staining and western blotting experiments.. ECH suppressed the proliferation, invasiveness and migration of GBM cells in vitro, as well as the growth of U87 xenograft in vivo. In addition, ECH downregulated the skp2 protein, EMT-related markers (vimentin and snail) and stemness markers (sox2 and Nestin). The inhibitory effects of ECH were augmented in the skp2-knockdown GBM cells, and reversed in cells with ectopic expression of skp2.. ECH inhibits glioma development by suppressing skp2-induced EMT of GBM cells.

Topics: Brain Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Glioblastoma; Glioma; Glycosides; Humans; Nestin; S-Phase Kinase-Associated Proteins; Sincalide; Vimentin

Glioblastoma (GBM) is the most common primary malignant brain tumor that leads to lethality. Several studies have demonstrated that mitochondria play an important role in GBM and that mitochondria-related genes (MRGs) are potential therapeutic targets. However, the role of MRGs in GBM remains unclear.. Differential expression and univariate Cox regression analyses were combined to screen for prognostic differentially-expressed (DE)-MRGs in GBM. Based on LASSO Cox analysis, 12 DE-MRGs were selected to construct a risk score model. Survival, time dependent ROC, and stratified analyses were performed to evaluate the performance of this risk model. Mutation and functional enrichment analyses were performed to determine the potential mechanism of the risk score. Immune cell infiltration analysis was used to determine the association between the risk score and immune cell infiltration levels. CCK-8 and transwell assays were performed to evaluate cell proliferation and migration, respectively. Mitochondrial reactive oxygen species (ROS) levels and morphology were measured using a confocal laser scanning microscope. Genes and proteins expression levels were investigated by quantitative PCR and western blotting, respectively.. We identified 21 prognostic DE-MRGs, of which 12 DE-MRGs were selected to construct a prognostic risk score model for GBM. This model presented excellent performance in predicting the prognosis of patients with GBM and acted as an independent predictive factor. Functional enrichment analysis revealed that the risk score was enriched in the inflammatory response, extracellular matrix, and pro-cancer-related and immune related pathways. Additionally, the risk score was significantly associated with gene mutations and immune cell infiltration in GBM. Single-stranded DNA-binding protein 1 (SSBP1) was considerably upregulated in GBM and associated with poor prognosis. Furthermore, SSBP1 knockdown inhibited GBM cell progression and migration. Mechanistically, SSBP1 knockdown resulted in mitochondrial dysfunction and increased ROS levels, which, in turn, increased temozolomide (TMZ) sensitivity in GBM cells by enhancing ferroptosis.. Our 12 DE-MRGs-based prognostic model can predict the GBM patients prognosis and 12 MRGs are potential targets for the treatment of GBM. SSBP1 was significantly upregulated in GBM and protected U87 cells from TMZ-induced ferroptosis, which could serve as a prognostic and therapeutic target/biomarker for GBM.

Topics: Biomarkers; DNA-Binding Proteins; Ferroptosis; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Mitochondria; Mitochondrial Proteins; Reactive Oxygen Species; Sincalide; Temozolomide

Prevention of the nuclear translocation of ANXA1 with Tat-NTS was recently reported to alleviate neuronal injury and protect against cerebral stroke. However, the role that Tat-NTS plays in the occurrence and development of gliomas still needs to be elucidated. Therefore, human glioblastoma (GB) cells were treated with various concentrations of Tat-NTS for 24 h, and cell proliferation, migration and invasion were assessed with CCK-8 and Transwell assays. The nuclear translocation of ANXA1 was evaluated by subcellular extraction and immunofluorescence, and protein expression levels were detected by Western blot analysis. In addition, the activity of MMP-2/9 was measured by gelatin zymography. The results revealed that Tat-NTS significantly inhibited the nuclear translocation of ANXA1 in U87 cells and inhibited the proliferation, migration and invasion of GB cells. Tat-NTS also suppressed cell cycle regulatory proteins and MMP-2/-9 activity and expression. Moreover, Tat-NTS reduced the level of p-p65 NF-κB in U87 cells. These results suggest that the Tat-NTS-induced inhibition of GB cell proliferation, migration and invasion is closely associated with the induction of cell cycle arrest, downregulation of MMP-2/-9 expression and activity and suppression of the NF-κB signaling pathway. Thus, Tat-NTS may be a potential chemotherapeutic agent for the treatment of GB.

Topics: Annexin A1; Cell Cycle Proteins; Cell Line, Tumor; Cell Movement; Cell Proliferation; Gelatin; Glioblastoma; Humans; Matrix Metalloproteinase 2; Neoplasm Invasiveness; NF-kappa B; Sincalide

Temozolomide (TMZ) is the preferred chemotherapeutic drug approved for the Glioblastoma multiforme (GBM) treatment. However, resistance to TMZ is the most intractable challenge for treatment of GBM. Screening of miRNAs is becoming a novel strategy to reveal underlying mechanism of drug-resistance of human tumors.. We conducted RNA sequencing (RNA-seq) for GBM cells treated continuously with TMZ 1 or 2 week or not. Bioinformatic analysis was used to predict targets of these altered miRNAs. Subsequently, we studied the potential role of miR-1268a in TMZ-resistance of GBM cells.. Expression levels of 55 miRNAs were identified altering both after 1 and 2 weeks TMZ treatment. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to illuminate the biological implication and related pathways of predicted target genes. We showed that miR-1268a was downregulated after TMZ treatment and targeted ABCC1/MRP1, a membrane transporter contributing to drug resistance, using dual-luciferase assay. Furthermore, we confirmed overexpression of miR-1268a inhibited protein translation of ABCC1 and restored upregulated expression of ABCC1 due to TMZ. Inversely, knockdown of miR-1268a increased ABCC1 at protein level and enhanced upregulation of ABCC1 with TMZ treatment. In addition, our data indicated that miR-1268a enhanced TMZ sensitivity in GBM cells.. Through RNA-seq analysis, we discovered miR-1268a and elucidated its role in modulating TMZ-resistance of GBM cells by targeting ABCC1.

Topics: Animals; Antineoplastic Agents, Alkylating; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Kaplan-Meier Estimate; Mice, Nude; Microarray Analysis; MicroRNAs; Multidrug Resistance-Associated Proteins; RNA, Messenger; Sincalide; Temozolomide; Time Factors; Transfection; Xenograft Model Antitumor Assays

MicroRNAs(miR) play an important role in cell growth, differentiation, proliferation and apoptosis, which can function either as oncogenes or as tumor suppressors in their effect on tumor growth. Smad3 is often underexpressed in very diverse types of malignant tumors and has an important tumor suppressive function; however, the underlying mechanism in solid cancer including glioblastomas(GBM) is not fully explored. The aim of this study is to explore the role of miR-92b in regulation of smad3 in GBM. In our study, we found that miR-92b expression was significantly increased in GBM tissues compared with normal brain tissues by Q-RT-PCR and in situ hybridization (P<0.01). However, expression of smad3 in GBM samples was significantly reduced compared with normal brain tissues by western blot and immunohistochemistry (P<0.05). Using 3'UTR luciferase reporter gene assay, we found that miR-92b directly affected smad3 expression in GBM cells by targeting the 3'-untranslated region. Silencing of miR-92b was able to significantly inhibit the viability of GBM cells in three GBM cell lines through up-regulating the TGF-beta/smad3/p21 signaling pathway in vitro. Furthermore, the tumor growth and the weight of U87 cells in the miR-92b inhibitor group were significantly inhibited when compared with that of the control group in vivo. Our data demonstrated that miR-92b may be considered as a tumor oncogene to promote GBM cell proliferation, and thus may serve as a potentially useful target for development of miRNA-based therapies in the future.

Topics: Animals; Apoptosis; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p21; Female; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Luciferases; Mice; Mice, Nude; MicroRNAs; Oligonucleotides; RNA, Messenger; RNA, Small Interfering; Sincalide; Smad3 Protein; Time Factors; Transfection; Xenograft Model Antitumor Assays

We have investigated the potential role of gastrin in the regulation of cell growth in human astrocytic tumors. To this end we have used synthetic analogs of gastrin and cholecystokinin (CCK) which behave as gastrin and/or CCK antagonists, e.g. compounds JMV-97, JMV-209 and JMV-179. Their effects on astrocytic tumor cell proliferation was investigated by the use of the colorimetric MTT assay. The in vitro biological models used in the present study included the SW1088, U87 and U373 astrocytic tumor cell lines. The results demonstrated marked influence of gastrin and CCK antagonists in the regulation of astrocytic tumor growth. This suggests that gastrin and/or CCK antagonists might be tested in experimental glioblastoma.

Topics: Astrocytes; Astrocytoma; Brain Neoplasms; Cholecystokinin; Gastrins; Glioblastoma; Humans; Peptide Fragments; Sincalide; Tumor Cells, Cultured