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1.
Anticancer Res ; 40(9): 4895-4905, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878777

RESUMO

BACKGROUND/AIM: Nicotinamide phosphoribosyl-transferase (NAMPT) is a rate-limiting enzyme in the pathway synthesizing nicotinamide adenine dinucleotide (NAD (+)) from nicotinamide (NAM). Glioma tissues exhibit up-regulated NAMPT expression associated with a poor prognosis of patients. To determine if NAMPT can be a molecular therapeutic target, we investigated the effects of short hairpin RNA (shRNA)-mediated NAMPT down-regulation. MATERIALS AND METHODS: We designed shRNA to NAMPT and transfected to T98G cells. The characteristics of these cells were analyzed. RESULTS: The NAMPT shRNA-transfected cells exhibited delayed cell growth. However, there was no difference in the increase of sensitivity to temozolomide (TMZ) or X-ray irradiation between the NAMPT and scramble shRNA-transfected cells. The expression of NAMPT in the NAMPT shRNA-transfected cells increased with cell passage. Additionally, the shRNA-mediated transfection was associated with enhanced expression of quinolinic acid phosphoribo-syltransferase (QPRT). CONCLUSION: shRNA-mediated NAMPT down-regulation may not decrease the NADt to a sufficient level to increase TMZ/radiation sensitivity.


Assuntos
Citocinas/metabolismo , Regulação para Baixo , Glioma/enzimologia , Nicotinamida Fosforribosiltransferase/metabolismo , Antineoplásicos Alquilantes/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Citocinas/genética , Glioma/metabolismo , Glioma/patologia , Humanos , NAD/metabolismo , Nicotinamida Fosforribosiltransferase/genética , Pentosiltransferases/genética , Pentosiltransferases/metabolismo , RNA Interferente Pequeno/genética , Temozolomida/farmacologia
2.
Life Sci ; 256: 117897, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32502543

RESUMO

Glioma is the most common brain malignancy and surgical resection is the primary option for patient with glioma. Anesthetics could be used to inhibit cancer dissemination and metastasis during surgery. This study aims to assess the function of volatile anesthetic sevoflurane in glioma migration and invasion and explore the potential mechanism. Twenty-five patients with glioma were recruited in this study. LN229 and U251 cells were used in vitro experiments. Cell viability was analyzed by MTT analysis. Cell migration and invasion were examined via transwell analysis. microRNA-34a-5p (miR-34a-5p) and matrix metalloproteinase-2 (MMP-2) levels were measured via quantitative real-time polymerase chain reaction. The relationship of miR-34a-5p and MMP-2 was tested via bioinformatics analysis, luciferase reporter analysis, RNA immunoprecipitation and RNA pull-down. Sevoflurane decreased glioma cell migration and invasion. In glioma cells, sevoflurane up-regulated miR-34a-5p abundance and down-regulated MMP-2 level. Overexpression of miR-34a-5p contributed to sevoflurane-caused suppression of migration and invasion, while its knockdown played an opposite effect. MMP-2 was targeted via miR-34a-5p and MMP-2 silence reversed the influence of miR-34a-5p knockdown under sevoflurane. Sevoflurane exposure represses cell migration and invasion, which might be related to inhibition of MMP-2 by up-regulating miR-34a-5p. This study provides a novel mechanism for understanding the pharmacological effects of sevoflurane on glioma.


Assuntos
Neoplasias Encefálicas/patologia , Movimento Celular/efeitos dos fármacos , Glioma/patologia , Metaloproteinase 2 da Matriz/metabolismo , MicroRNAs/metabolismo , Sevoflurano/farmacologia , Sequência de Bases , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Glioma/enzimologia , Glioma/genética , Humanos , MicroRNAs/genética , Invasividade Neoplásica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Regulação para Cima/efeitos dos fármacos
3.
Am Soc Clin Oncol Educ Book ; 40: 1-8, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32186930

RESUMO

Since the first discovery of isocitrate dehydrogenase (IDH) mutations in cancer, considerable progress has been made in our understanding of their contribution to cancer development. For glioma, this has helped to identify two diagnostic groups of tumors (oligodendroglioma and astrocytoma IDHmt) with distinct clinical characteristics and that are now diagnosed by the presence of the IDH mutations. The metabolic changes occurring as the consequence of the altered substrate affinity of the mutant IDH protein results in a cascade of intracellular changes, also inducing a relative sensitivity to chemotherapy and radiotherapy compared with IDHwt tumors. Pharmacologic blockade of the mutant enzyme with first-in-class inhibitors has been efficacious for the treatment of IDH-mutant acute myeloid leukemia (AML) and is currently being evaluated in phase III trials for IDH-mutant glioma (INDIGO) and cholangiocarcinoma (ClarIDHy). It seems likely that acquired resistance to mutant IDH inhibitors will eventually emerge, and combination therapies to augment the antitumor activity of mutant IDH inhibitors have already been initiated. Approaches to exploit, rather than inhibit, the unique metabolism of IDH-mutant cancer cells have emerged from laboratory studies and are now also being tested in the clinic. Results of these clinical trials are eagerly awaited and will likely provide new key insights and direction of the treatment of IDH-mutant human cancer.


Assuntos
Neoplasias Encefálicas/genética , Glioma/genética , Substância Cinzenta/patologia , Isocitrato Desidrogenase/genética , Mutação , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/patologia , Glioma/enzimologia , Glioma/patologia , Humanos
4.
Biochem Biophys Res Commun ; 524(3): 723-729, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32035622

RESUMO

Recent research has revealed that glioblastoma (GBM) avoids the immune system via strong expression of indoleamine 2,3-dioxygenase 1 (IDO1). IDO1, an enzyme involved in tryptophan metabolism, is now proposed as a new target in GBM treatment, since several reports have demonstrated that IDO1 expression is related to GBM malignancy. On the other hand, it is well known that glioma stem cells (GSCs) are strongly related to the malignancy of GBM. However, there is as yet no report evaluating the relationship between GSCs and IDO1. We therefore examined the expression levels of IDO1 in GSCs in order to identify a new therapeutic target for GBM based on the immune systems of GSCs. In the present study, we employed human GBM cell lines (U-138MG, U-251MG) and patient-derived GSC model cell lines (0125-GSC, 0222-GSC). GSC model cell lines Rev-U-138MG and Rev-U-251MG were established by culturing U-138MG and U-251MG in serum-free media, while differentiated GBM model cell lines 0125-DGC and 0222-DGC were established by culturing 0125-GSC and 0222-GSC in serum-containing media. The expression levels of stem cell markers (Nanog, Nestin, Oct4 and Sox2) and IDO1 protein and mRNA were determined. Rev-U-138MG and Rev-U-251MG formed spheres and their expression levels of stem cell markers were increased as compared to U-138MG and U-251MG. On the other hand, 0125-DGC and 0222-DGC suffered breakdown of sphere formation, despite the original 0125-GSC and 0222-GSC forming spheres, and their expression levels of the markers were decreased. IDO1 expressions were strongly recognized in Rev-U-138MG, Rev-U-251MG, 0125-GSC and 0222-GSC as compared to U-138MG, U-251MG, 0125-DGC and 0222-DGC. These findings demonstrate that GSCs exhibit treatment resistance with immunosuppression via high expression levels of IDO1, and could represent a novel target for GBM treatment.


Assuntos
Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/patologia , Glioma/enzimologia , Glioma/patologia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Células-Tronco Neoplásicas/enzimologia , Células-Tronco Neoplásicas/patologia , Linhagem Celular Tumoral , Meios de Cultura Livres de Soro , Glioblastoma/patologia , Humanos , Interferon beta/metabolismo
5.
Adv Exp Med Biol ; 1202: 151-178, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32034713

RESUMO

Protein tyrosine kinases are enzymes that are capable of adding a phosphate group to specific tyrosines on target proteins. A receptor tyrosine kinase (RTK) is a tyrosine kinase located at the cellular membrane and is activated by binding of a ligand via its extracellular domain. Protein phosphorylation by kinases is an important mechanism for communicating signals within a cell and regulating cellular activity; furthermore, this mechanism functions as an "on" or "off" switch in many cellular functions. Ninety unique tyrosine kinase genes, including 58 RTKs, were identified in the human genome; the products of these genes regulate cellular proliferation, survival, differentiation, function, and motility. Tyrosine kinases play a critical role in the development and progression of many types of cancer, in addition to their roles as key regulators of normal cellular processes. Recent studies have revealed that RTKs such as epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), c-Met, Tie, Axl, discoidin domain receptor 1 (DDR1), and erythropoietin-producing human hepatocellular carcinoma (Eph) play a major role in glioma invasion. Herein, we summarize recent advances in understanding the role of RTKs in glioma pathobiology, especially the invasive phenotype, and present the perspective that RTKs are a potential target of glioma therapy.


Assuntos
Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/patologia , Glioma/enzimologia , Glioma/patologia , Receptores Proteína Tirosina Quinases/metabolismo , Animais , Neoplasias Encefálicas/tratamento farmacológico , Movimento Celular , Proliferação de Células , Glioma/tratamento farmacológico , Humanos , Fosforilação , Fosfotirosina/metabolismo , Receptores Proteína Tirosina Quinases/antagonistas & inibidores
6.
Adv Exp Med Biol ; 1202: 259-279, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32034718

RESUMO

Signal transduction pathways directly communicate and transform chromatin to change the epigenetic landscape and regulate gene expression. Chromatin acts as a dynamic platform of signal integration and storage. Histone modifications and alteration of chromatin structure play the main role in chromatin-based gene expression regulation. Alterations in genes coding for histone modifying enzymes and chromatin modifiers result in malfunction of proteins that regulate chromatin modification and remodeling. Such dysregulations culminate in profound changes in chromatin structure and distorted patterns of gene expression. Gliomagenesis is a multistep process, involving both genetic and epigenetic alterations. Recent applications of next generation sequencing have revealed that many chromatin regulation-related genes, including ATRX, ARID1A, SMARCA4, SMARCA2, SMARCC2, BAF155 and hSNF5 are mutated in gliomas. In this review we summarize newly identified mechanisms affecting expression or functions of selected histone modifying enzymes and chromatin modifiers in gliomas. We focus on selected examples of pathogenic mechanisms involving ATRX, histone methyltransferase G9a, histone acetylases/deacetylases and chromatin remodeling complexes SMARCA2/4. We discuss the impact of selected epigenetics alterations on glioma pathobiology, signaling and therapeutic responses. We assess the attempts of targeting defective pathways with new inhibitors.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Cromatina/metabolismo , Glioma/tratamento farmacológico , Glioma/patologia , Histonas/metabolismo , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/genética , Cromatina/genética , Montagem e Desmontagem da Cromatina/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Glioma/enzimologia , Glioma/genética , Código das Histonas/efeitos dos fármacos , Histonas/química , Humanos
7.
Neoplasma ; 67(2): 371-378, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31986891

RESUMO

Glutamine addiction is a major feature of glioma cells and plays an important role in its growth and proliferation. GLUL (glutamate-ammonia ligase), which catalyzes glutamate and ammonia to synthesize glutamine, plays a crucial role in tumor growth and proliferation. We attempt to determine a pathway that limits the growth of glioma by targeting GLUL and explore effective strategies blocking glutamine metabolism. We note that miRNAs mediate regulation of genes participating directly or indirectly in cancer cell metabolism. The regulatory roles of miRNAs on metabolic enzymes are widely discussed, however miRNAs regulation of glutamine metabolism by targeting GLUL in glioma has not yet been reported. Here, we examined both the expression and functions of GLUL in glioma cells. Findings indicated that the expression of GLUL was upregulated in high-grade compared to low-grade glioma cells. Knockdown of GLUL effectively inhibited proliferation, migration and invasion of glioma cells in vitro. Bioinformatics analyses, as well as dual-luciferase reporter assays, revealed that miR-140-5p bound to GLUL mRNA at the 3'-UTR location. Furthermore, the proliferation, migration and invasion of glioma cells were also repressed by miR-140-5p. Overall, these results showed that miR-140-5p exerted its inhibitory effects on proliferation, migration and invasion in glioma cells through downregulating GLUL. Thus, the miR-140-5p/GLUL axis may function as a potential target for glioma treatment.


Assuntos
Glioma/patologia , Glutamato-Amônia Ligase/genética , MicroRNAs/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Glioma/enzimologia , Humanos , Invasividade Neoplásica
8.
World Neurosurg ; 133: e421-e427, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31526886

RESUMO

BACKGROUND: In the era of integrated genomic-histologic analysis of brain tumors, new biomarkers have been introduced as diagnostic, prognostic, and therapeutic indicators. The analysis of the mutation in the isocitrate dehydrogenase (IDH) genes IDH1 and IDH2 has provided important diagnostic and prognostic information for patients affected by diffuse glioma (i.e., the presence of the mutation has been related to an increased survival rate). The reference standard of IDH mutation detection has been its assessment in surgical specimens, immunohistochemistry, and/or genetic sequencing. Knowing the IDH status information preoperatively would be of great importance, because it has been related to tumor progression and the response to treatment. The oncometabolite 2-hydroxyglutarate (2HG), accumulated in gliomas with IDH mutation status, can be detected in vivo using magnetic resonance spectroscopy (MRS). METHODS: The 2HG-MRS technique remains technically challenging. We have summarized the results of the first pilot study in Australia, which included 10 patients affected by glioma. The data recorded from May 2017 to November 2018 were analyzed. RESULTS: In our exploratory study, we reached a sensitivity and specificity of 100%, confirming the strong predictive role of 2HG, as detected using MRS, in the diagnosis of glioma. CONCLUSION: In the present study, we have focused on methodological tips and future perspectives of the technique in the neuroimaging and neuro-oncological scenario. We would advocate the integration of 2HG-MRS into standard clinical practice.


Assuntos
Neoplasias Encefálicas/enzimologia , Análise Mutacional de DNA/métodos , Glioma/enzimologia , Isocitrato Desidrogenase/análise , Espectroscopia de Ressonância Magnética/métodos , Proteínas de Neoplasias/análise , Neuroimagem/métodos , Adulto , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Feminino , Previsões , Glioma/diagnóstico por imagem , Glioma/genética , Glioma/patologia , Humanos , Isocitrato Desidrogenase/genética , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas de Neoplasias/genética , Neuroimagem/tendências , Projetos Piloto , Sensibilidade e Especificidade , Adulto Jovem
9.
Molecules ; 24(23)2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31771098

RESUMO

The identification of signaling pathways that are involved in gliomagenesis is crucial for targeted therapy design. In this study we assessed the biological and therapeutic effect of ingenol-3-dodecanoate (IngC) on glioma. IngC exhibited dose-time-dependent cytotoxic effects on large panel of glioma cell lines (adult, pediatric cancer cells, and primary cultures), as well as, effectively reduced colonies formation. Nevertheless, it was not been able to attenuate cell migration, invasion, and promote apoptotic effects when administered alone. IngC exposure promoted S-phase arrest associated with p21CIP/WAF1 overexpression and regulated a broad range of signaling effectors related to survival and cell cycle regulation. Moreover, IngC led glioma cells to autophagy by LC3B-II accumulation and exhibited increased cytotoxic sensitivity when combined to a specific autophagic inhibitor, bafilomycin A1. In comparison with temozolomide, IngC showed a mean increase of 106-fold in efficacy, with no synergistic effect when they were both combined. When compared with a known compound of the same class, namely ingenol-3-angelate (I3A, Picato®), IngC showed a mean 9.46-fold higher efficacy. Furthermore, IngC acted as a potent inhibitor of protein kinase C (PKC) activity, an emerging therapeutic target in glioma cells, showing differential actions against various PKC isotypes. These findings identify IngC as a promising lead compound for the development of new cancer therapy and they may guide the search for additional PKC inhibitors.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/enzimologia , Diterpenos/farmacologia , Euphorbia/química , Glioma/enzimologia , Proteína Quinase C/antagonistas & inibidores , Antineoplásicos/química , Autofagia , Neoplasias Encefálicas/tratamento farmacológico , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diterpenos/química , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/tratamento farmacológico , Humanos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Transdução de Sinais/efeitos dos fármacos
10.
Anal Bioanal Chem ; 411(30): 7929-7933, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31754769

RESUMO

Knowledge of the isocitrate dehydrogenase (IDH) mutation status of glioma patients could provide insights for decision-making during brain surgery. However, pathology is not able to provide such information intraoperatively. Here we describe the first application of a miniature mass spectrometer (MS) to the determination of IDH mutation status in gliomas intraoperatively. The instrumentation was modified to be compatible with use in the operating room. Tandem MS was performed on the oncometabolite, 2-hydroxyglutarate, and a reference metabolite, glutamate, which is not involved in the IDH mutation. Ratios of fragment ion intensities were measured to calculate an IDH mutation score, which was used to differentiate IDH mutant and wild-type tissues. The results of analyzing 25 biopsies from 13 patients indicate that reliable determination of IDH mutation status was achieved (p = 0.0001, using the Kruskal-Wallis non-parametric test). With its small footprint and low power consumption and noise level, this application of miniature mass spectrometers represents a simple and cost-effective platform for an important intraoperative measurement. Graphical abstract.


Assuntos
Neoplasias Encefálicas/enzimologia , Glioma/enzimologia , Isocitrato Desidrogenase/genética , Mutação , Espectrometria de Massas por Ionização por Electrospray/instrumentação , Espectrometria de Massas em Tandem/instrumentação , Biópsia , Neoplasias Encefálicas/patologia , Estudos de Coortes , Glioma/patologia , Humanos , Período Intraoperatório
11.
Eur J Pharmacol ; 863: 172665, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31542479

RESUMO

Glioma is one of the most lethal malignancies and molecular regulators driving gliomagenesis are incompletely understood. Although temozolomide (TMZ) has been applied for malignant gliomas as a canonical chemotherapy, the treatment of glioma still remains limited due to frequently developed resistance to TMZ. Therefore, promising strategies that sensitize glioma cells to temozolomide are overwhelming to develop. Here we found that the expression of dihydrofolate reductase (DHFR) and thymidylate synthetase (TYMS), which played an essential role in folate metabolism and several types of tumors, were up-regulated in both human glioma tissues and cell lines, and overexpression of DHFR/TYMS promoted the proliferation of glioma cells. Notably, inhibition of DHFR/TYMS by pemetrexed exhibited synergistic anti-glioma activity with TMZ in both cell lines and U251 xenografts, which suggested potential combined chemotherapy for glioma. Mechanistically, the synergistic effect of inhibition of DHFR/TYMS with TMZ was due to activated AMPK and subsequently suppressed mTOR signaling pathway. Taken together, these findings identify an uncharacterized role of DHFR/TYMS in glioma growth and TMZ sensitivity mediated by AMPK-mTOR signal pathway, and provide a prospective approach for improving the anti-tumor activity of TMZ in glioma.


Assuntos
Glioma/patologia , Temozolomida/farmacologia , Tetra-Hidrofolato Desidrogenase/metabolismo , Timidilato Sintase/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Antagonistas do Ácido Fólico/farmacologia , Glioma/tratamento farmacológico , Glioma/enzimologia , Humanos , Camundongos , Terapia de Alvo Molecular , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Timidilato Sintase/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Mol Cell Biochem ; 462(1-2): 195-206, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31493190

RESUMO

Thymoquinone (TQ) is a highly perspective chemotherapeutic agent against gliomas and glioblastomas because of its ability to cross the blood-brain barrier and its selective cytotoxicity for glioblastoma cells compared to primary astrocytes. Here, we tested the hypothesis that TQ-induced mild oxidative stress provokes C6 glioma cell apoptosis through redox-dependent alteration of MAPK proteins. We showed that low concentrations of TQ (20-50 µM) promoted cell-cycle arrest and induced hydrogen peroxide generation as a result of NADH-quinone oxidoreductase 1-catalyzed two-electron reduction of this quinone. Similarly, low concentrations of TQ efficiently conjugated intracellular GSH disturbing redox state of glioma cells and provoking mitochondrial dysfunction. We demonstrated that high concentrations of TQ (70-100 µM) induced reactive oxygen species generation due to its one-electron reduction. TQ provoked apoptosis in C6 glioma cells through mitochondrial potential dissipation and permeability transition pore opening. The identified TQ modes of action on C6 glioma cells open up the possibility of considering it as a promising agent to enhance the sensitivity of cancer cells to standard chemotherapeutic drugs.


Assuntos
Apoptose/efeitos dos fármacos , Benzoquinonas/farmacologia , Glioma/patologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Benzoquinonas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Glioma/enzimologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Oxirredução , Fosfatidilinositol 3-Quinases/metabolismo , Ratos
13.
Biomed Pharmacother ; 118: 109369, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31545229

RESUMO

The main characteristic of glioma is recurrence, even after intensive multidisciplinary treatment. Studies show that enhanced invasive ability will increase the ability of tumor cells to escape from the primary tumor mass, which is a key factor contributing to tumor relapse and recurrence. In this study, we assessed the expression of MMP-2, MMP-9, two important matrix metallopeptidases that increase the invasive ability of glioma, and their suppressors, TIMP-1, TIMP-2 in glioma tissues from primary and recurrent glioma patients by immunohistochemistry. Glioma cells and nude mice were used for in vitro and in vivo studies. Results showed that the expression of MMP-2 and MMP-9 in recurrent gliomas were significantly higher than those in primary gliomas (P = 3.075 × 10-11, P = 1.510 × 10-5, respectively). We also found that radiotherapy increased the expression of MMP-9, but had no effect on MMP-2 and TIMP-1/2. With glioma cell line U251, we found that irradiation increased the expression of MMP-9 in vitro. Tumor tissues from an orthotopic xenograft model showed that after irradiation treatment, the expression of MMP-9 increased significantly in vivo. We also found that knocking down MMP-9 decreased irradiation-induced invasion obviously. Above all, we concluded that higher expressions of MMP-2/-9 indicate poor prognosis in glioma recurrence. The increased expression of MMP-9 after radiotherapy suggests that MMP-9 might be an important target in the radiosensitization of glioma.


Assuntos
Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/enzimologia , Glioma/diagnóstico , Glioma/enzimologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Criança , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Recidiva Local de Neoplasia/enzimologia , Recidiva Local de Neoplasia/patologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Prognóstico , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Adulto Jovem
14.
Genes Dev ; 33(19-20): 1428-1440, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31488577

RESUMO

The histone methyltransferase activity of PRC2 is central to the formation of H3K27me3-decorated facultative heterochromatin and gene silencing. In addition, PRC2 has been shown to automethylate its core subunits, EZH1/EZH2 and SUZ12. Here, we identify the lysine residues at which EZH1/EZH2 are automethylated with EZH2-K510 and EZH2-K514 being the major such sites in vivo. Automethylated EZH2/PRC2 exhibits a higher level of histone methyltransferase activity and is required for attaining proper cellular levels of H3K27me3. While occurring independently of PRC2 recruitment to chromatin, automethylation promotes PRC2 accessibility to the histone H3 tail. Intriguingly, EZH2 automethylation is significantly reduced in diffuse intrinsic pontine glioma (DIPG) cells that carry a lysine-to-methionine substitution in histone H3 (H3K27M), but not in cells that carry either EZH2 or EED mutants that abrogate PRC2 allosteric activation, indicating that H3K27M impairs the intrinsic activity of PRC2. Our study demonstrates a PRC2 self-regulatory mechanism through its EZH1/2-mediated automethylation activity.


Assuntos
Glioma/enzimologia , Glioma/genética , Histonas/metabolismo , Criança , Ativação Enzimática , Inativação Gênica , Histonas/genética , Humanos , Lisina/metabolismo , Metilação , Complexo Repressor Polycomb 2/metabolismo , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo
15.
Oncogene ; 38(41): 6794-6800, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31399646

RESUMO

Spermidine/spermine N1-acetyltransferase 1 (SAT1), the rate-limiting enzyme in polyamine catabolism, has broad regulatory roles due to near ubiquitous polyamine binding. We describe a novel function of SAT1 as a gene-specific transcriptional regulator through local polyamine acetylation. SAT1 expression is elevated in aggressive brain tumors and promotes resistance to radiotherapy. Expression profiling in glioma cells identified SAT1 target genes that distinguish high- and low-grade tumors, in support of the prognostic utility of SAT1 expression. We further discovered mechanisms of SAT1-driven tumor aggressiveness through promotion of expression of both DNA damage response pathways as well as cell cycle regulatory genes. Mechanistically, SAT1 associates specifically with the promoter of the MELK gene, which functionally controls other SAT1 targets, and leads biologically to maintenance of neurosphere stemness in conjunction with FOXM1 and EZH2. CRISPR knockin mutants demonstrate the essentiality of the polyamine acetyltransferase activity of SAT1 for its function as a transcriptional regulator. Together, the data demonstrate that gene-specific polyamine removal is a major transcriptional regulatory mechanism active in high-grade gliomas that drives poor outcomes.


Assuntos
Neoplasias Encefálicas/patologia , Glioma/patologia , Transcrição Genética , Acetiltransferases/genética , Acetiltransferases/metabolismo , Neoplasias Encefálicas/enzimologia , Cromatina/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Glioma/enzimologia , Humanos , Células-Tronco Neoplásicas/patologia , Proteínas Serina-Treonina Quinases/metabolismo
16.
Int J Oncol ; 55(1): 59-68, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31180529

RESUMO

The present study investigated the effects of the combined treatment of two peptide nucleic acids (PNAs), directed against microRNAs involved in caspase­3 mRNA regulation (miR­155­5p and miR­221­3p) in the temozolomide (TMZ)­resistant T98G glioma cell line. These PNAs were conjugated with an octaarginine tail in order to obtain an efficient delivery to treated cells. The effects of singularly administered PNAs or a combined treatment with both PNAs were examined on apoptosis, with the aim to determine whether reversion of the drug­resistance phenotype was obtained. Specificity of the PNA­mediated effects was analyzed by reverse transcription­quantitative polymerase­chain reaction, which demonstrated that the effects of R8­PNA­a155 and R8-PNA-a221 anti­miR PNAs were specific. Furthermore, the results obtained confirmed that both PNAs induced apoptosis when used on the temozolomide­resistant T98G glioma cell line. Notably, co­administration of both anti­miR­155 and anti­miR­221 PNAs was associated with an increased proapoptotic activity. In addition, TMZ further increased the induction of apoptosis in T98G cells co­treated with anti­miR­155 and anti­miR­221 PNAs.


Assuntos
Caspase 3/metabolismo , Glioma/tratamento farmacológico , Glioma/genética , MicroRNAs/antagonistas & inibidores , Ácidos Nucleicos Peptídicos/farmacologia , Temozolomida/farmacologia , Antineoplásicos Alquilantes/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Glioma/enzimologia , Humanos , MicroRNAs/genética , Ácidos Nucleicos Peptídicos/genética
17.
Cancer Cell ; 35(6): 868-884.e6, 2019 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-31185211

RESUMO

Heterotypic interactions across diverse cell types can enable tumor progression and hold the potential to expand therapeutic interventions. Here, combined profiling and functional studies of glioma cells in glioblastoma multiforme (GBM) models establish that PTEN deficiency activates YAP1, which directly upregulates lysyl oxidase (LOX) expression. Mechanistically, secreted LOX functions as a potent macrophage chemoattractant via activation of the ß1 integrin-PYK2 pathway in macrophages. These infiltrating macrophages secrete SPP1, which sustains glioma cell survival and stimulates angiogenesis. In PTEN-null GBM models, LOX inhibition markedly suppresses macrophage infiltration and tumor progression. Correspondingly, YAP1-LOX and ß1 integrin-SPP1 signaling correlates positively with higher macrophage density and lower overall survival in GBM patients. This symbiotic glioma-macrophage interplay provides therapeutic targets specifically for PTEN-deficient GBM.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Glioma/genética , Macrófagos/enzimologia , PTEN Fosfo-Hidrolase/genética , Comunicação Parácrina , Proteína-Lisina 6-Oxidase/metabolismo , Mutações Sintéticas Letais , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Antineoplásicos/farmacologia , Biomarcadores Tumorais/deficiência , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/patologia , Movimento Celular , Proliferação de Células , Inibidores Enzimáticos/farmacologia , Feminino , Quinase 2 de Adesão Focal/genética , Quinase 2 de Adesão Focal/metabolismo , Regulação Neoplásica da Expressão Gênica , Glioma/tratamento farmacológico , Glioma/enzimologia , Glioma/patologia , Células HEK293 , Humanos , Integrina beta1/genética , Integrina beta1/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos SCID , Osteopontina/genética , Osteopontina/metabolismo , PTEN Fosfo-Hidrolase/deficiência , Comunicação Parácrina/efeitos dos fármacos , Proteína-Lisina 6-Oxidase/antagonistas & inibidores , Proteína-Lisina 6-Oxidase/genética , Células RAW 264.7 , Transdução de Sinais , Células THP-1 , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Carga Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Nucl Med Commun ; 40(8): 850-856, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31135693

RESUMO

OBJECTIVE: We evaluate the O6-methylguanylmethyltransferase (MGMT) methylation status noninvasively by analyzing radiomics features of C-methionine (MET) PET images, which may reflect the detailed biological properties of gliomas. PATIENTS AND METHODS: Fifty-seven patients with histopathologically confirmed gliomas, who were initially examined with C-MET PET/MR were retrospectively enrolled. Quantitative uptake of MET was assessed using conventional, histogram and texture features. These features were compared between the two groups classified by MGMT promoter methylation status. RESULTS: The histogram features (Skewness and Kurtosis) of the MGMT methylated group were significantly higher than those of the MGMT unmethylated group (Skewness: 0.90 ± 0.71 vs. 0.49 ± 0.45; P = 0.01) (Kurtosis: 1.36 ± 2.30 vs. 0.08 ± 0.65; P = 0.003), but there were no significant differences in Skewness or Kurtosis between the groups in glioma-grade-matched subgroup analysis. Moreover, there was no significant difference in other features between the methylated group and unmethylated group. CONCLUSION: The histogram features (Skewness and Kurtosis) of MET PET/MRI may be two key indicators to detect MGMT methylation status in gliomas and valuable predictors for the clinical responses of patients scheduled to receive temozolomide chemotherapeutics.


Assuntos
Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glioma/diagnóstico por imagem , Glioma/genética , Imagem por Ressonância Magnética , Metionina , Tomografia por Emissão de Pósitrons , Proteínas Supressoras de Tumor/genética , Adulto , Feminino , Glioma/enzimologia , Humanos , Masculino , Imagem Multimodal , Regiões Promotoras Genéticas/genética , Estudos Retrospectivos
19.
Biomed Pharmacother ; 116: 108524, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31108349

RESUMO

Glioma is the most common form of malignant brain cancer with high mortality rate in human. Therefore, finding effective therapeutic strategy and revealing the underlying molecular mechanism is necessary. Ampelopsin (Amp), an effective component of the traditional Chinese herb of Ampelopsis grossedentata, is reported to have important biological properties, including anti-inflammatory, anti-cancer, and anti-oxidant activity; however, its effects on human glioma are poorly understood. Here, the in vitro and in vivo study was performed to investigate the anti-glioma ability of Ampelopsin. Human glioma cell lines of U251 and A172 were treated with Ampelopsin (0, 25, 50, and 100 uM) for 24 h, followed by various analysis. And human glioma xenograft models were established by injecting U251, accompanied with administration of Ampelopsin at 50 and 100 mg/kg to confirm the anti-cancer role of Ampelopsin. We found that Ampelopsin could suppress the glioma cell proliferation by modulating G1 and S phase arrest. Incubation with Ampelopsin led to the activity of Caspase-8, Caspase-9, Caspase-3 and poly (ADP-ribose) polymerases (PARP), indicating that Ampelopsin induced apoptotic response via both intrinsic and extrinsic signaling pathways. Additionally, autophagy was also observed in Ampelopsin-treated cancer cells, which is evidenced by autophagosome formation and LC3B-II accumulation. Ampelopsin-caused cancer cell death was obviously regained by apoptosis inhibitors. Further, Ampelopsin activated c-Jun N-terminal protein kinase (JNK) expression and enhanced reactive oxygen species (ROS) generation. Suppressing JNK markedly ameliorated Ampelopsin-induced apoptosis and autophagy, and ROS scavenger exhibited similar results. In vivo, Ampelopsin inhibited tumor growth and progression in mouse xenograft models. In conclusion, our findings indicated that Ampelopsin led to G1 and S phase arrest, triggered apoptosis and autophagy through potentiating ROS generation and JNK activation in human glioma cells. Thus, Ampelopsin might be a promising candidate against human glioma.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/patologia , Flavonoides/farmacologia , Glioma/enzimologia , Glioma/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Flavonoides/química , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Fosforilação/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Pathologe ; 40(Suppl 1): 9-17, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31025086

RESUMO

BACKGROUND: Diffuse astrocytic and oligodendroglial gliomas are the most common neuroepithelial tumors. Their classification is based on the integration of histological and molecular findings according to the classification of tumors of the central nervous system published by the World Health Organization (WHO) in 2016. OBJECTIVES: This review describes the different entities and variants of diffuse gliomas and summarizes the current diagnostic criteria for these tumors. MATERIALS AND METHODS: Based on the 2016 WHO classification and selected other publications, the histomolecular diagnostics of diffuse gliomas is presented and illustrated. RESULTS: Diffuse gliomas are divided into isocitrate dehydrogenase (IDH)-mutant or IDH-wildtype gliomas by detection of mutations in the IDH1 or IDH2 genes. Among the IDH-mutant gliomas, oligodendroglial tumors are characterized by combined losses of chromosome arms 1p and 19q. Loss of nuclear expression of the ATRX protein is a marker of IDH- mutant astrocytic gliomas. Glioblastoma, IDH-wildtype, is the most common diffuse glioma. Diffuse and anaplastic astrocytic gliomas without IDH mutation should be further evaluated for molecular features of glioblastoma, IDH-wildtype. Diffuse gliomas in the thalamus, brainstem, or spinal cord carrying a histone 3 (H3)-K27M mutation are classified as diffuse midline gliomas, H3-K27M-mutant. By determining the IDH and 1p/19q status, oligoastrocytomas can be stratified into either astrocytic or oligodendroglial gliomas. Gliomatosis cerebri is no longer regarded as a distinct glioma entity. CONCLUSIONS: Diffuse gliomas can today be classified accurately and reproducibly by means of histological, immunohistochemical, and molecular analyses.


Assuntos
Astrócitos/patologia , Neoplasias Encefálicas/diagnóstico , Glioma/diagnóstico , Oligodendroglioma/patologia , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Glioma/enzimologia , Glioma/genética , Glioma/patologia , Humanos , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Mutação , Proteína Nuclear Ligada ao X/metabolismo
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