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1.
Int J Mol Sci ; 22(19)2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34638754

RESUMO

Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. Radiotherapy has long been an important treatment method of GBM. However, the intrinsic radioresistance of GBM cells is a key reason of poor therapeutic efficiency. Recently, many studies have shown that using the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) in radiotherapy may improve the prognosis of GBM patients, but the underlying molecular mechanisms remain unclear. In this study, Gene Expression Omnibus (GEO) datasets GSE153982 and GSE131956 were analyzed to evaluate radiation-induced changes of gene expression in GBM without or with SAHA treatment, respectively. Additionally, the survival-associated genes of GBM patients were screened using the Chinese Glioma Genome Atlas (CGGA) database. Taking the intersection of these three datasets, 11 survival-associated genes were discovered to be activated by irradiation and regulated by SAHA. The expressions of these genes were further verified in human GBM cell lines U251, T98G, and U251 homologous radioresistant cells (U251R) by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). It was found that MMP14 mRNA was considerably highly expressed in the radioresistant cell lines and was reduced by SAHA treatment. Transfection of MMP14 siRNA (siMMP14) suppressed cell survivals of these GBM cells after irradiation. Taken together, our results reveal for the first time that the MMP14 gene contributed to SAHA-induced radiosensitization of GBM.


Assuntos
Quimiorradioterapia , Bases de Dados de Ácidos Nucleicos , Glioblastoma , Inibidores de Histona Desacetilases/farmacologia , Metaloproteinase 14 da Matriz/metabolismo , Proteínas de Neoplasias/metabolismo , Tolerância a Radiação/efeitos dos fármacos , Vorinostat/farmacologia , Linhagem Celular Tumoral , Glioblastoma/enzimologia , Glioblastoma/genética , Glioblastoma/terapia , Humanos , Metaloproteinase 14 da Matriz/genética , Proteínas de Neoplasias/genética , Vorinostat/farmacocinética
2.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360836

RESUMO

Lysyl oxidase-like 3 (LOXL3), belonging to the lysyl oxidase family, is responsible for the crosslinking in collagen or elastin. The cellular localization of LOXL3 is in the extracellular space by reason of its canonical function. In tumors, the presence of LOXL3 has been associated with genomic stability, cell proliferation, and metastasis. In silico analysis has shown that glioblastoma was among tumors with the highest LOXL3 expression levels. LOXL3 silencing of U87MG cells by siRNA led to the spreading of the tumor cell surface, and the transcriptome analysis of these cells revealed an upregulation of genes coding for extracellular matrix, cell adhesion, and cytoskeleton components, convergent to an increase in cell adhesion and a decrease in cell invasion observed in functional assays. Significant correlations of LOXL3 expression with genes coding for tubulins were observed in the mesenchymal subtype in the TCGA RNA-seq dataset of glioblastoma (GBM). Conversely, genes involved in endocytosis and lysosome formation, along with MAPK-binding proteins related to focal adhesion turnover, were downregulated, which may corroborate the observed decrease in cell viability and increase in the rate of cell death. Invasiveness is a major determinant of the recurrence and poor outcome of GBM patients, and downregulation of LOXL3 may contribute to halting the tumor cell invasion.


Assuntos
Aminoácido Oxirredutases/metabolismo , Adesão Celular , Regulação Neoplásica da Expressão Gênica , Glioblastoma/enzimologia , Aminoácido Oxirredutases/genética , Aminoácido Oxirredutases/fisiologia , Linhagem Celular Tumoral , Proliferação de Células , Simulação por Computador , Citoesqueleto/metabolismo , Endocitose , Matriz Extracelular/metabolismo , Perfilação da Expressão Gênica , Glioblastoma/genética , Glioblastoma/patologia , Glioblastoma/fisiopatologia , Humanos , Lisossomos/fisiologia , Invasividade Neoplásica
3.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209254

RESUMO

Glioblastoma multiforme (GBM) is a malignant primary brain tumor. The 5-year relative survival rate of patients with GBM remains <30% on average despite aggressive treatments, and secondary therapy fails in 90% of patients. In chemotherapeutic failure, detoxification proteins are crucial to the activity of chemotherapy drugs. Usually, glutathione S-transferase (GST) superfamily members act as detoxification enzymes by activating xenobiotic metabolites through conjugation with glutathione in healthy cells. However, some overexpressed GSTs not only increase GST activity but also trigger chemotherapy resistance and tumorigenesis-related signaling transductions. Whether GSTM3 is involved in GBM chemoresistance remains unclear. In the current study, we found that T98G, a GBM cell line with pre-existing temozolomide (TMZ) resistance, has high glycolysis and GSTM3 expression. GSTM3 knockdown in T98G decreased glycolysis ability through lactate dehydrogenase A activity reduction. Moreover, it increased TMZ toxicity and decreased invasion ability. Furthermore, we provide next-generation sequencing-based identification of significantly changed messenger RNAs of T98G cells with GSTM3 knockdown for further research. GSTM3 was downregulated in intrinsic TMZ-resistant T98G with a change in the expression levels of some essential glycolysis-related genes. Thus, GSTM3 was associated with glycolysis in chemotherapeutic resistance in T98G cells. Our findings provide new insight into the GSTM3 mechanism in recurring GBM.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Glioblastoma/enzimologia , Glutationa Transferase/metabolismo , Glicólise , Proteínas de Neoplasias/metabolismo , Temozolomida , Linhagem Celular Tumoral , Glioblastoma/genética , Glioblastoma/patologia , Glutationa Transferase/genética , Humanos , Proteínas de Neoplasias/genética
4.
Bioengineered ; 12(1): 3934-3946, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34288811

RESUMO

Glioblastoma (GBM) is a common malignant tumor of the brain. Members of the carbohydrate sulfotransferase (CHST) family are deregulated in various cancer types. However, limited data are available on the role of the members of the CHST family in the development of GBM. The present study aimed to identify the role of significant members of the CHST family in GBM and explore the effects and molecular mechanisms of these significant members on GBM cell proliferation and mobility. In the current study, we demonstrated that CHST12 is the only member of CHST family that is upregulated in GBM tissues and associated with a lower survival rate according to the data obtained from The Cancer Genome Atlas. Similarly, the expression of CHST12 increased in GBM tissues than in adjacent tissues and had an important diagnostic value in distinguishing tumor tissues from adjacent tissues. The high expression of CHST12 indicated a lower overall survival rate, was negatively associated with the Karnofsky Performance Scale score, was positively associated with the KI67 expression rate, and was an independent risk factor for GBM. Knockdown of CHST12 significantly decreased GBM cell proliferation and mobility and inhibited the Wnt/ß-catenin pathway. Restoration of ß-catenin expression in GBM cells reversed the inhibitory effects of CHST12 knockdown on GBM cell proliferation and mobility. In conclusion, the present study demonstrated that CHST12 may be a novel biomarker for GBM; it regulates GBM cell proliferation and mobility via the WNT/ß-catenin pathway.


Assuntos
Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/patologia , Movimento Celular , Técnicas de Silenciamento de Genes , Glioblastoma/enzimologia , Glioblastoma/patologia , Sulfotransferases/deficiência , Via de Sinalização Wnt , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Humanos , Masculino , Pessoa de Meia-Idade , Sulfotransferases/genética , Sulfotransferases/metabolismo , Análise de Sobrevida , Regulação para Cima/genética
5.
PLoS One ; 16(7): e0241092, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34234350

RESUMO

Tumor cells tend to metabolize glucose through aerobic glycolysis instead of oxidative phosphorylation in mitochondria. One of the rate limiting enzymes of glycolysis is 6-phosphofructo-1-kinase, which is allosterically activated by fructose 2,6-bisphosphate which in turn is produced by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2 or PFKFB). Mounting evidence suggests that cancerous tissues overexpress the PFKFB isoenzyme, PFKFB3, being causing enhanced proliferation of cancer cells. Initially, six PFKFB3 splice variants with different C-termini have been documented in humans. More recently, additional splice variants with varying N-termini were discovered the functions of which are to be uncovered. Glioblastoma is one of the deadliest forms of brain tumors. Up to now, the role of PFKFB3 splice variants in the progression and prognosis of glioblastomas is only partially understood. In this study, we first re-categorized the PFKFB3 splice variant repertoire to simplify the denomination. We investigated the impact of increased and decreased levels of PFKFB3-4 (former UBI2K4) and PFKFB3-5 (former variant 5) on the viability and proliferation rate of glioblastoma U87 and HEK-293 cells. The simultaneous knock-down of PFKFB3-4 and PFKFB3-5 led to a decrease in viability and proliferation of U87 and HEK-293 cells as well as a reduction in HEK-293 cell colony formation. Overexpression of PFKFB3-4 but not PFKFB3-5 resulted in increased cell viability and proliferation. This finding contrasts with the common notion that overexpression of PFKFB3 enhances tumor growth, but instead suggests splice variant-specific effects of PFKFB3, apparently with opposing effects on cell behaviour. Strikingly, in line with this result, we found that in human IDH-wildtype glioblastomas, the PFKFB3-4 to PFKFB3-5 ratio was significantly shifted towards PFKFB3-4 when compared to control brain samples. Our findings indicate that the expression level of distinct PFKFB3 splice variants impinges on tumorigenic properties of glioblastomas and that splice pattern may be of important diagnostic value for glioblastoma.


Assuntos
Glioblastoma/enzimologia , Fosfofrutoquinase-2/metabolismo , Neoplasias Encefálicas/metabolismo , Glicólise , Células HEK293 , Humanos , Isoenzimas/metabolismo
6.
Mol Cell ; 81(13): 2722-2735.e9, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34077757

RESUMO

Lipid droplets are important for cancer cell growth and survival. However, the mechanism underlying the initiation of lipid droplet lipolysis is not well understood. We demonstrate here that glucose deprivation induces the binding of choline kinase (CHK) α2 to lipid droplets, which is sequentially mediated by AMPK-dependent CHKα2 S279 phosphorylation and KAT5-dependent CHKα2 K247 acetylation. Importantly, CHKα2 with altered catalytic domain conformation functions as a protein kinase and phosphorylates PLIN2 at Y232 and PLIN3 at Y251. The phosphorylated PLIN2/3 dissociate from lipid droplets and are degraded by Hsc70-mediated autophagy, thereby promoting lipid droplet lipolysis, fatty acid oxidation, and brain tumor growth. In addition, levels of CHKα2 S279 phosphorylation, CHKα2 K247 acetylation, and PLIN2/3 phosphorylation are positively correlated with one another in human glioblastoma specimens and are associated with poor prognosis in glioblastoma patients. These findings underscore the role of CHKα2 as a protein kinase in lipolysis and glioblastoma development.


Assuntos
Colina Quinase/metabolismo , Glioblastoma/enzimologia , Gotículas Lipídicas/enzimologia , Lipólise , Proteínas de Neoplasias/metabolismo , Proteínas Quinases/metabolismo , Acetilação , Linhagem Celular Tumoral , Colina Quinase/genética , Glioblastoma/genética , Humanos , Proteínas de Neoplasias/genética , Proteínas Quinases/genética
7.
J Med Chem ; 64(12): 8599-8606, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34096701

RESUMO

Glioblastoma multiforme (GBM) is a highly invasive and aggressive malignant glioma. Current treatment modalities are unable to significantly prolong survival in patients diagnosed with glioblastoma, so more effective strategies of antitumor treatments are in urgent demand. Here, we found that lysosomal sulfatase expression was significantly correlated with poor prognosis of GBM. Hence, a new probe, MNG, was developed with a new protocol utilizing glucose groups to detect lysosomal sulfatase. It also exhibits potential for monitoring GBM cells, depending on the hyperactive lysosomal sulfatase expression of tumor cells. Meantime, we identified that sulbactam as the first reported lysosomal sulfatase inhibitor inhibits the tumor growth of GBM. Collectively, our work highlights that lysosomal sulfatase was detected using a new protocol and its potential as a therapeutic target in GBM and reveals a distinct mechanism that sulbactam inhibits cell proliferation related to lysosomal sulfatase, indicating that sulbactam could be a promising therapeutic agent against GBM.


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Glioblastoma/tratamento farmacológico , Sulbactam/farmacologia , Sulfatases/antagonistas & inibidores , Linhagem Celular Tumoral , Corantes Fluorescentes/química , Glioblastoma/diagnóstico , Glioblastoma/enzimologia , Glucosídeos/química , Humanos , Lisossomos/enzimologia , Naftalimidas/química , Prognóstico , Sulfatases/análise , Sulfatases/química
8.
Biomed Pharmacother ; 140: 111766, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34082401

RESUMO

The protein L-isoaspartyl (D-aspartyl) methyltransferase (PIMT) recognizes abnormal L-isoaspartyl and D-aspartyl residues in proteins. Among examined tissues, PIMT shows the highest level in the brain. The U-87 MG cell line is a commonly used cellular model to study the most frequent brain tumor, glioblastoma. Previously, we reported that PIMT amount increased when U-87 MG cells were detached from the extracellular matrix. Recently, we also showed that PIMT possessed pro-angiogenic properties. Together, these PIMT features led us to postulate that PIMT could play a critical role in glioblastoma growth. Here, we investigate PIMT role in U-87 MG cell viability, adhesion, migration, invasion, and colony formation and in the reorganization of the actin and tubulin cytoskeleton. PIMT inhibition by siRNA significantly reduced in vitro cell migration and invasion in various assays, including wound-healing assay, Boyden chambers coated with gelatin and Matrigel invasion assay. Conversely, in stably transfected U-87 MG cells overexpressing wild-type PIMT, cell migration, invasive capacity and colony formation significantly increased. However, in stably transfected cells with the gene encoding for mutated PIMT(D83V), despite of its overexpression, migration and invasion remained similar to those observed in control cells. In all these conditions, cell viability was unaffected. Importantly, overexpressed wild-type PIMT and mutated PIMT(D83V) have opposite effects on the organization of microtubules and actin cytoskeleton and thus on morphology of U-87 cells. These data highlighted the importance of PIMT level and its catalytic activity in migration and invasion of U-87 glioma cells and its possible contribution in cancer invasion during glioma growth.


Assuntos
Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/patologia , Glioblastoma/enzimologia , Glioblastoma/patologia , Proteína D-Aspartato-L-Isoaspartato Metiltransferase/metabolismo , Adesão Celular , Linhagem Celular Tumoral , Movimento Celular , Sobrevivência Celular , Humanos , Proteína D-Aspartato-L-Isoaspartato Metiltransferase/genética , RNA Interferente Pequeno/genética
9.
Biomolecules ; 11(5)2021 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-34065652

RESUMO

Isocitrate dehydrogenase (IDH1) catalyzes the reversible NADP+-dependent oxidation of isocitrate to α-ketoglutarate (αKG). IDH1 mutations, primarily R132H, drive > 80% of low-grade gliomas and secondary glioblastomas and facilitate the NADPH-dependent reduction of αKG to the oncometabolite D-2-hydroxyglutarate (D2HG). While the biochemical features of human WT and mutant IDH1 catalysis have been well-established, considerably less is known about mechanisms of regulation. Proteomics studies have identified lysine acetylation in WT IDH1, indicating post-translational regulation. Here, we generated lysine to glutamine acetylation mimic mutants in IDH1 to evaluate the effects on activity. We show that mimicking lysine acetylation decreased the catalytic efficiency of WT IDH1, with less severe catalytic consequences for R132H IDH1.


Assuntos
Neoplasias Encefálicas/enzimologia , Glioblastoma/enzimologia , Glioma/enzimologia , Isocitrato Desidrogenase/metabolismo , Mutação , Processamento de Proteína Pós-Traducional , Acetilação , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Simulação por Computador , Glioblastoma/genética , Glioblastoma/patologia , Glioma/genética , Glioma/patologia , Humanos , Mutagênese Sítio-Dirigida , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade
10.
Cancer Sci ; 112(7): 2835-2844, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33932065

RESUMO

This study aims to build a radiological model based on standard MR sequences for detecting methylguanine methyltransferase (MGMT) methylation in gliomas using texture analysis. A retrospective cross-sectional study was undertaken in a cohort of 53 glioma patients who underwent standard preoperative magnetic resonance (MR) imaging. Conventional visual radiographic features and clinical factors were compared between MGMT promoter methylated and unmethylated groups. Texture analysis extracted the top five most powerful texture features of MR images in each sequence quantitatively for detecting the MGMT promoter methylation status. The radiomic signature (Radscore) was generated by a linear combination of the five features and estimates in each sequence. The combined model based on each Radscore was established using multivariate logistic regression analysis. A receiver operating characteristic (ROC) curve, nomogram, calibration, and decision curve analysis (DCA) were used to evaluate the performance of the model. No significant differences were observed in any of the visual radiographic features or clinical factors between different MGMT methylated statuses. The top five most powerful features were selected from a total of 396 texture features of T1, contrast-enhanced T1, T2, and T2 FLAIR. Each sequence's Radscore can distinguish MGMT methylated status. A combined model based on Radscores showed differentiation between methylated MGMT and unmethylated MGMT both in the glioblastoma (GBM) dataset as well as the dataset for all other gliomas. The area under the ROC curve values for the combined model was 0.818, with 90.5% sensitivity and 72.7% specificity, in the GBM dataset, and 0.833, with 70.2% sensitivity and 90.6% specificity, in the overall gliomas dataset. Nomogram, calibration, and DCA also validated the performance of the combined model. The combined model based on texture features could be considered as a noninvasive imaging marker for detecting MGMT methylation status in glioma.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/enzimologia , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Glioma/diagnóstico por imagem , Glioma/enzimologia , Proteínas Supressoras de Tumor/metabolismo , Adulto , Idoso , Neoplasias Encefálicas/patologia , Meios de Contraste , Estudos Transversais , Metilação de DNA , Reparo do DNA , Técnicas de Apoio para a Decisão , Feminino , Glioblastoma/diagnóstico por imagem , Glioblastoma/enzimologia , Glioblastoma/patologia , Glioma/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Nomogramas , Curva ROC , Estudos Retrospectivos , Sensibilidade e Especificidade , Adulto Jovem
11.
Molecules ; 26(7)2021 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-33800655

RESUMO

Maintenance of Na+ and K+ gradients across the cell plasma membrane is an essential process for mammalian cell survival. An enzyme responsible for this process, sodium-potassium ATPase (NKA), has been currently extensively studied as a potential anticancer target, especially in lung cancer and glioblastoma. To date, many NKA inhibitors, mainly of natural origin from the family of cardiac steroids (CSs), have been reported and extensively studied. Interestingly, upon CS binding to NKA at nontoxic doses, the role of NKA as a receptor is activated and intracellular signaling is triggered, upon which cancer cell death occurs, which lies in the expression of different NKA isoforms than in healthy cells. Two major CSs, digoxin and digitoxin, originally used for the treatment of cardiac arrhythmias, are also being tested for another indication-cancer. Such drug repositioning has a big advantage in smoother approval processes. Besides this, novel CS derivatives with improved performance are being developed and evaluated in combination therapy. This article deals with the NKA structure, mechanism of action, activity modulation, and its most important inhibitors, some of which could serve not only as a powerful tool to combat cancer, but also help to decipher the so-far poorly understood NKA regulation.


Assuntos
Antineoplásicos/uso terapêutico , Digitoxina/uso terapêutico , Digoxina/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Ouabaína/uso terapêutico , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Animais , Antineoplásicos/química , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/patologia , Ensaios Clínicos como Assunto , Digitoxina/química , Digoxina/química , Reposicionamento de Medicamentos , Inibidores Enzimáticos/química , Glioblastoma/tratamento farmacológico , Glioblastoma/enzimologia , Glioblastoma/patologia , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/química , Isoenzimas/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Modelos Moleculares , Ouabaína/química , Ligação Proteica , Conformação Proteica , ATPase Trocadora de Sódio-Potássio/química , ATPase Trocadora de Sódio-Potássio/metabolismo
12.
Anticancer Res ; 41(4): 1859-1870, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33813391

RESUMO

BACKGROUND/AIM: Demethoxycurcumin (DMC), one of the derivatives of curcumin, has been shown to induce apoptotic cell death in many human cancer cell lines. However, there is no available information on whether DMC inhibits metastatic activity in human glioblastoma cancer cells in vitro. MATERIALS AND METHODS: DMC at 1.0-3.0 µM significantly decreased the proliferation of GBM 8401 cells; thus, we used 2.0 µM for further investigation regarding anti-metastatic activity in human glioblastoma GBM 8401 cells. RESULTS: The internalized amount of DMC has reached the highest level in GBM 8401 cells after 3 h treatment. Wound healing assay was used to determine cell mobility and results indicated that DMC suppressed cell movement of GBM 8401 cells. The transwell chamber assays were used for measuring cell migration and invasion and results indicated that DMC suppressed cell migration and invasion in GBM 8401 cells. Gelatin zymography assay was used to examine gelatinolytic activity (MMP-2) in conditioned media of GBM 8401 cells treated by DMC and results demonstrated that DMC significantly reduced MMP-2 activity. Western blotting showed that DMC reduced the levels of p-EGFR(Tyr1068), GRB2, Sos1, p-Raf, MEK, p-ERK1/2, PI3K, p-Akt/PKBα(Thr308), p-PDK1, NF-κB, TIMP-1, MMP-9, MMP-2, GSK3α/ß, ß-catenin, N-cadherin, and vimentin, but it elevated Ras and E-cadherin at 24 h treatment. CONCLUSION: DMC inhibited cancer cell migration and invasion through inhibition of PI3K/Akt and NF-κB signaling pathways in GBM 8401 cells. We suggest that DMC may be used as a novel anti-metastasis agent for the treatment of human glioblastoma cancer in the future.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diarileptanoides/farmacologia , Glioblastoma/tratamento farmacológico , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Glioblastoma/enzimologia , Glioblastoma/patologia , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , NF-kappa B/metabolismo , Invasividade Neoplásica , Transdução de Sinais , beta Catenina/metabolismo
13.
Cells ; 10(3)2021 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-33810170

RESUMO

Cancer is a redox disease. Low levels of reactive oxygen species (ROS) are beneficial for cells and have anti-cancer effects. ROS are produced in the mitochondria during ATP production by oxidative phosphorylation (OXPHOS). In the present review, we describe ATP production in primary brain tumors, glioblastoma, in relation to ROS production. Differentiated glioblastoma cells mainly use glycolysis for ATP production (aerobic glycolysis) without ROS production, whereas glioblastoma stem cells (GSCs) in hypoxic periarteriolar niches use OXPHOS for ATP and ROS production, which is modest because of the hypoxia and quiescence of GSCs. In a significant proportion of glioblastoma, isocitrate dehydrogenase 1 (IDH1) is mutated, causing metabolic rewiring, and all cancer cells use OXPHOS for ATP and ROS production. Systemic therapeutic inhibition of glycolysis is not an option as clinical trials have shown ineffectiveness or unwanted side effects. We argue that systemic therapeutic inhibition of OXPHOS is not an option either because the anti-cancer effects of ROS production in healthy cells is inhibited as well. Therefore, we advocate to remove GSCs out of their hypoxic niches by the inhibition of their binding to niches to enable their differentiation and thus increase their sensitivity to radiotherapy and/or chemotherapy.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/enzimologia , Metabolismo Energético , Glioblastoma/enzimologia , Isocitrato Desidrogenase/metabolismo , Células-Tronco Neoplásicas/enzimologia , Animais , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Metabolismo Energético/efeitos dos fármacos , Predisposição Genética para Doença , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Isocitrato Desidrogenase/genética , Terapia de Alvo Molecular , Mutação , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Fenótipo , Espécies Reativas de Oxigênio/metabolismo , Efeito Warburg em Oncologia
14.
Cell Death Dis ; 12(3): 271, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33723235

RESUMO

Cancers, including glioblastoma multiforme (GBM), undergo coordinated reprogramming of metabolic pathways that control glycolysis and oxidative phosphorylation (OXPHOS) to promote tumor growth in diverse tumor microenvironments. Adaptation to limited nutrient availability in the microenvironment is associated with remodeling of mitochondrial morphology and bioenergetic capacity. We recently demonstrated that NF-κB-inducing kinase (NIK) regulates mitochondrial morphology to promote GBM cell invasion. Here, we show that NIK is recruited to the outer membrane of dividing mitochondria with the master fission regulator, Dynamin-related protein1 (DRP1). Moreover, glucose deprivation-mediated metabolic shift to OXPHOS increases fission and mitochondrial localization of both NIK and DRP1. NIK deficiency results in decreased mitochondrial respiration, ATP production, and spare respiratory capacity (SRC), a critical measure of mitochondrial fitness. Although IκB kinase α and ß (IKKα/ß) and NIK are required for OXPHOS in high glucose media, only NIK is required to increase SRC under glucose deprivation. Consistent with an IKK-independent role for NIK in regulating metabolism, we show that NIK phosphorylates DRP1-S616 in vitro and in vivo. Notably, a constitutively active DRP1-S616E mutant rescues oxidative metabolism, invasiveness, and tumorigenic potential in NIK-/- cells without inducing IKK. Thus, we establish that NIK is critical for bioenergetic stress responses to promote GBM cell pathogenesis independently of IKK. Our data suggest that targeting NIK may be used to exploit metabolic vulnerabilities and improve therapeutic strategies for GBM.


Assuntos
Neoplasias Encefálicas/enzimologia , Metabolismo Energético , Glioblastoma/enzimologia , Mitocôndrias/enzimologia , Proteínas Serina-Treonina Quinases/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Dinaminas/genética , Dinaminas/metabolismo , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Mitocôndrias/genética , Mitocôndrias/patologia , Dinâmica Mitocondrial , Membranas Mitocondriais/enzimologia , Membranas Mitocondriais/patologia , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Microambiente Tumoral
15.
Cochrane Database Syst Rev ; 3: CD013316, 2021 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-33710615

RESUMO

BACKGROUND: Glioblastoma is an aggressive form of brain cancer. Approximately five in 100 people with glioblastoma survive for five years past diagnosis. Glioblastomas that have a particular modification to their DNA (called methylation) in a particular region (the O6-methylguanine-DNA methyltransferase (MGMT) promoter) respond better to treatment with chemotherapy using a drug called temozolomide. OBJECTIVES: To determine which method for assessing MGMT methylation status best predicts overall survival in people diagnosed with glioblastoma who are treated with temozolomide. SEARCH METHODS: We searched MEDLINE, Embase, BIOSIS, Web of Science Conference Proceedings Citation Index to December 2018, and examined reference lists. For economic evaluation studies, we additionally searched NHS Economic Evaluation Database (EED) up to December 2014. SELECTION CRITERIA: Eligible studies were longitudinal (cohort) studies of adults with diagnosed glioblastoma treated with temozolomide with/without radiotherapy/surgery. Studies had to have related MGMT status in tumour tissue (assessed by one or more method) with overall survival and presented results as hazard ratios or with sufficient information (e.g. Kaplan-Meier curves) for us to estimate hazard ratios. We focused mainly on studies comparing two or more methods, and listed brief details of articles that examined a single method of measuring MGMT promoter methylation. We also sought economic evaluations conducted alongside trials, modelling studies and cost analysis. DATA COLLECTION AND ANALYSIS: Two review authors independently undertook all steps of the identification and data extraction process for multiple-method studies. We assessed risk of bias and applicability using our own modified and extended version of the QUality In Prognosis Studies (QUIPS) tool. We compared different techniques, exact promoter regions (5'-cytosine-phosphate-guanine-3' (CpG) sites) and thresholds for interpretation within studies by examining hazard ratios. We performed meta-analyses for comparisons of the three most commonly examined methods (immunohistochemistry (IHC), methylation-specific polymerase chain reaction (MSP) and pyrosequencing (PSQ)), with ratios of hazard ratios (RHR), using an imputed value of the correlation between results based on the same individuals. MAIN RESULTS: We included 32 independent cohorts involving 3474 people that compared two or more methods. We found evidence that MSP (CpG sites 76 to 80 and 84 to 87) is more prognostic than IHC for MGMT protein at varying thresholds (RHR 1.31, 95% confidence interval (CI) 1.01 to 1.71). We also found evidence that PSQ is more prognostic than IHC for MGMT protein at various thresholds (RHR 1.36, 95% CI 1.01 to 1.84). The data suggest that PSQ (mainly at CpG sites 74 to 78, using various thresholds) is slightly more prognostic than MSP at sites 76 to 80 and 84 to 87 (RHR 1.14, 95% CI 0.87 to 1.48). Many variants of PSQ have been compared, although we did not see any strong and consistent messages from the results. Targeting multiple CpG sites is likely to be more prognostic than targeting just one. In addition, we identified and summarised 190 articles describing a single method for measuring MGMT promoter methylation status. AUTHORS' CONCLUSIONS: PSQ and MSP appear more prognostic for overall survival than IHC. Strong evidence is not available to draw conclusions with confidence about the best CpG sites or thresholds for quantitative methods. MSP has been studied mainly for CpG sites 76 to 80 and 84 to 87 and PSQ at CpG sites ranging from 72 to 95. A threshold of 9% for CpG sites 74 to 78 performed better than higher thresholds of 28% or 29% in two of three good-quality studies making such comparisons.


Assuntos
Neoplasias Encefálicas/mortalidade , Metilação de DNA , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Glioblastoma/mortalidade , Regiões Promotoras Genéticas/genética , Proteínas Supressoras de Tumor/metabolismo , Adulto , Antineoplásicos Alquilantes/uso terapêutico , Viés , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/enzimologia , Estudos de Coortes , Ilhas de CpG/genética , Glioblastoma/tratamento farmacológico , Glioblastoma/enzimologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Reação em Cadeia da Polimerase/métodos , Valor Preditivo dos Testes , Prognóstico , Temozolomida/uso terapêutico
16.
Nat Cell Biol ; 23(3): 278-291, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33664496

RESUMO

Activated EGFR signalling drives tumorigenicity in 50% of glioblastoma (GBM). However, EGFR-targeting therapy has proven ineffective in treating patients with GBM, indicating that there is redundant EGFR activation. Circular RNAs are covalently closed RNA transcripts that are involved in various physiological and pathological processes. Herein, we report an additional activation mechanism of EGFR signalling in GBM by an undescribed secretory E-cadherin protein variant (C-E-Cad) encoded by a circular E-cadherin (circ-E-Cad) RNA through multiple-round open reading frame translation. C-E-Cad is overexpressed in GBM and promotes glioma stem cell tumorigenicity. C-E-Cad activates EGFR independent of EGF through association with the EGFR CR2 domain using a unique 14-amino-acid carboxy terminus, thereby maintaining glioma stem cell tumorigenicity. Notably, inhibition of C-E-Cad markedly enhances the antitumour activity of therapeutic anti-EGFR strategies in GBM. Our results uncover a critical role of C-E-Cad in stimulating EGFR signalling and provide a promising approach for treating EGFR-driven GBM.


Assuntos
Antígenos CD/metabolismo , Neoplasias Encefálicas/enzimologia , Caderinas/metabolismo , Glioblastoma/enzimologia , RNA Circular/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Antígenos CD/genética , Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Caderinas/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Camundongos Nus , Invasividade Neoplásica , RNA Circular/genética , Fator de Transcrição STAT3/genética , Transdução de Sinais , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Int J Mol Sci ; 22(4)2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33673213

RESUMO

Glioblastoma multiforme (GBM) is amongst the deadliest of human cancers, with a median survival rate of just over one year following diagnosis. Characterized by rapid proliferation and diffuse infiltration into the brain, GBM is notoriously difficult to treat, with tumor cells showing limited response to existing therapies and eventually developing resistance to these interventions. As such, there is intense interest in better understanding the molecular alterations in GBM to guide the development of more efficient targeted therapies. GBM tumors can be classified into several molecular subtypes which have distinct genetic signatures, and they show aberrant activation of numerous signal transduction pathways, particularly those connected to receptor tyrosine kinases (RTKs) which control glioma cell growth, survival, migration, invasion, and angiogenesis. There are also non-canonical modes of RTK signaling found in GBM, which involve G-protein-coupled receptors and calcium channels. This review uses The Cancer Genome Atlas (TCGA) GBM dataset in combination with a data-mining approach to summarize disease characteristics, with a focus on select molecular pathways that drive GBM pathogenesis. We also present a unique genomic survey of RTKs that are frequently altered in GBM subtypes, as well as catalog the GBM disease association scores for all RTKs. Lastly, we discuss current RTK targeted therapies and highlight emerging directions in GBM research.


Assuntos
Neoplasias Encefálicas/enzimologia , Proliferação de Células , Glioblastoma/enzimologia , Proteínas de Neoplasias/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Proteínas de Neoplasias/genética , Fosforilação/genética , Receptores Proteína Tirosina Quinases/genética
18.
Cell Death Dis ; 12(3): 251, 2021 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-33674562

RESUMO

Ciclopirox (CPX) is an antifungal drug that has recently been reported to act as a potential anticancer drug. However, the effects and underlying molecular mechanisms of CPX on glioblastoma multiforme (GBM) remain unknown. Bortezomib (BTZ) is the first proteasome inhibitor-based anticancer drug approved to treat multiple myeloma and mantle cell lymphoma, as BTZ exhibits toxic effects on diverse tumor cells. Herein, we show that CPX displays strong anti-tumorigenic activity on GBM. Mechanistically, CPX inhibits GBM cellular migration and invasion by reducing N-Cadherin, MMP9 and Snail expression. Further analysis revealed that CPX suppresses the expression of several key subunits of mitochondrial enzyme complex, thus leading to the disruption of mitochondrial oxidative phosphorylation (OXPHOS) in GBM cells. In combination with BTZ, CPX promotes apoptosis in GBM cells through the induction of reactive oxygen species (ROS)-mediated c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) signaling. Moreover, CPX and BTZ synergistically activates nuclear factor kappa B (NF-κB) signaling and induces cellular senescence. Our findings suggest that a combination of CPX and BTZ may serve as a novel therapeutic strategy to enhance the anticancer activity of CPX against GBM.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Bortezomib/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Ciclopirox/farmacologia , Glioblastoma/tratamento farmacológico , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Glioblastoma/enzimologia , Glioblastoma/patologia , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Fosforilação Oxidativa/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Biochem Pharmacol ; 186: 114437, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33571503

RESUMO

MerTK has been identified as a promising target for therapeutic intervention in glioblastoma. Genetic studies documented a range of oncogenic processes that MerTK targeting could influence, however robust pharmacological validation has been missing. The aim of this study was to assess therapeutic potential of MerTK inhibitors in glioblastoma therapy. Unlike previous studies, our work provides several lines of evidence that MerTK activity is dispensable for glioblastoma growth. We observed heterogeneous responses to MerTK inhibitors that could not be correlated to MerTK inhibition or MerTK expression in cells. The more selective MerTK inhibitors UNC2250 and UNC2580A lack the anti-proliferative potency of less-selective inhibitors exemplified by UNC2025. Functional assays in MerTK-high and MerTK-deficient cells further demonstrate that the anti-cancer efficacy of UNC2025 is MerTK-independent. However, despite its efficacy in vitro, UNC2025 failed to attenuate glioblastoma growth in vivo. Gene expression analysis from cohorts of glioblastoma patients identified that MerTK expression correlates negatively with proliferation and positively with quiescence genes, suggesting that MerTK regulates dormancy rather than proliferation in glioblastoma. In summary, this study demonstrates the importance of orthogonal inhibitors and disease-relevant models in target validation studies and raises a possibility that MerTK inhibitors could be used to target dormant glioblastoma cells.


Assuntos
Proliferação de Células/fisiologia , Glioblastoma/enzimologia , Células-Tronco Neoplásicas/enzimologia , c-Mer Tirosina Quinase/antagonistas & inibidores , c-Mer Tirosina Quinase/biossíntese , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cicloexanóis/farmacologia , Relação Dose-Resposta a Droga , Glioblastoma/patologia , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
20.
Eur J Pharmacol ; 897: 173936, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33581134

RESUMO

Glioblastoma Multiforme (GBM) is a highly invasive primary brain tumour characterized by chemo- and radio-resistance and poor overall survival. GBM can present an aberrant functionality of p53, caused by the overexpression of the murine double minute 2 protein (MDM2) and its analogue MDM4, which may influence the response to conventional therapies. Moreover, tumour resistance/invasiveness has been recently attributed to an overexpression of the chemokine receptor CXCR4, identified as a pivotal mediator of glioma neovascularization. Notably, CXCR4 and MDM2-4 cooperate in promoting tumour invasion and progression. Although CXCR4 actively promotes MDM2 activation leading to p53 inactivation, MDM2-4 knockdown induces the downregulation of CXCR4 gene transcription. Our study aimed to assess if the CXCR4 signal blockade could enhance glioma cells' sensitivity to the inhibition of the p53-MDMs axis. Rationally designed inhibitors of MDM2/4 were combined with the CXCR4 antagonist, AMD3100, in human GBM cells and GBM stem-like cells (neurospheres), which are crucial for tumour recurrence and chemotherapy resistance. The dual MDM2/4 inhibitor RS3594 and the CXCR4 antagonist AMD3100 reduced GBM cell invasiveness and migration in single-agent treatment and mainly in combination. AMD3100 sensitized GBM cells to the antiproliferative activity of RS3594. It is noteworthy that these two compounds present synergic effects on cancer stem components: RS3594 inhibited the growth and formation of neurospheres, AMD3100 induced differentiation of neurospheres while enhancing RS3594 effectiveness preventing their proliferation/clonogenicity. These results confirm that blocking CXCR4/MDM2/4 represents a valuable strategy to reduce GBM proliferation and invasiveness, acting on the stem cell component too.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Benzilaminas/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Proteínas de Ciclo Celular/antagonistas & inibidores , Ciclamos/farmacologia , Glioblastoma/tratamento farmacológico , Indóis/farmacologia , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Receptores CXCR4/antagonistas & inibidores , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Glioblastoma/enzimologia , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Invasividade Neoplásica , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/enzimologia , Células-Tronco Neoplásicas/patologia , Neurogênese/efeitos dos fármacos , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Receptores CXCR4/metabolismo , Transdução de Sinais , Esferoides Celulares , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
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