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1.
Int J Mol Sci ; 22(7)2021 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-33804873

RESUMEN

Different functional states determine glioblastoma (GBM) heterogeneity. Brain cancer cells coexist with the glial cells in a functional syncytium based on a continuous metabolic rewiring. However, standard glioma therapies do not account for the effects of the glial cells within the tumor microenvironment. This may be a possible reason for the lack of improvements in patients with high-grade gliomas therapies. Cell metabolism and bioenergetic fitness depend on the availability of nutrients and interactions in the microenvironment. It is strictly related to the cell location in the tumor mass, proximity to blood vessels, biochemical gradients, and tumor evolution, underlying the influence of the context and the timeline in anti-tumor therapeutic approaches. Besides the cancer metabolic strategies, here we review the modifications found in the GBM-associated glia, focusing on morphological, molecular, and metabolic features. We propose to analyze the GBM metabolic rewiring processes from a systems biology perspective. We aim at defining the crosstalk between GBM and the glial cells as modules. The complex networking may be expressed by metabolic modules corresponding to the GBM growth and spreading phases. Variation in the oxidative phosphorylation (OXPHOS) rate and regulation appears to be the most important part of the metabolic and functional heterogeneity, correlating with glycolysis and response to hypoxia. Integrated metabolic modules along with molecular and morphological features could allow the identification of key factors for controlling the GBM-stroma metabolism in multi-targeted, time-dependent therapies.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Microambiente Tumoral , Animales , Neoplasias Encefálicas/patología , Glioblastoma/patología , Humanos , Hipoxia Tumoral
2.
Anticancer Res ; 41(4): 1811-1819, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813386

RESUMEN

BACKGROUND/AIM: Glioblastoma is the most common cancer among primary brain tumors, however, its prognosis and treatment advances are very poor. Here, we investigated whether c-Met, FOLR1, and AXL proteins are promising targets for chimeric antigen receptor (CAR) T-cell therapy, for they are known to be over-expressed in a variety of solid tumors. MATERIALS AND METHODS: CAR constructs were prepared and CAR KHYG-1 cells targeting c-Met, FOLR1, or AXL were made by lentiviral transduction. The activity of CAR KHYG-1 cells against cancer cells was measured by cytokine secretion and cell lysis assays. RESULTS: c-Met and AXL were over-expressed in most glioblastoma cell lines (11/13), but not in neuroblastoma cell lines (0/8). FOLR1 was over-expressed only in one among 16 glioblastoma cell lines. Our antigen-specific CAR KHYG-1 cells eradicated target positive glioblastoma cells selectively. CONCLUSION: Anti-c-Met and anti-AXL CAR NK or T cells could be effective in glioblastoma cells.


Asunto(s)
Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Inmunoterapia Adoptiva , Células Asesinas Naturales/inmunología , Proteínas Proto-Oncogénicas c-met/inmunología , Proteínas Proto-Oncogénicas/inmunología , Proteínas Tirosina Quinasas Receptoras/inmunología , Receptores Quiméricos de Antígenos/inmunología , Linfocitos T/inmunología , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Técnicas de Cocultivo , Citocinas/metabolismo , Citotoxicidad Inmunológica , Receptor 1 de Folato/inmunología , Receptor 1 de Folato/metabolismo , Glioblastoma/inmunología , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Células Jurkat , Células Asesinas Naturales/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-met/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/metabolismo , Linfocitos T/metabolismo
3.
Int J Mol Sci ; 22(7)2021 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-33807400

RESUMEN

Many exogenous and endogenous risk factors have been proposed as precursors of brain tumors, including the exposure to non-ionizing electromagnetic fields. Nevertheless, there is still a debate among the scientific community about the hazard of the effects produced by non-ionizing radiation (NIR) because conflicting results have been found (number of articles reviewed >50). For that reason, to provide new evidence on the possible effects produced by exposure to NIR, we performed different studies with several combinations of extremely low frequencies, times, and field intensities in tumoral and non-tumoral cells. The results of our studies showed that cell viability was frequency dependent in glioblastoma cells. In fact, our results revealed that a frequency of 30 Hz-or even other frequencies close to 30 Hz-could constitute a window frequency determinant of the cellular response in tumoral and non-tumoral cells.


Asunto(s)
Supervivencia Celular/efectos de la radiación , Campos Electromagnéticos/efectos adversos , Radiación no Ionizante/efectos adversos , Animales , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Glioblastoma/metabolismo , Humanos , Ratones
4.
Nat Commun ; 12(1): 1912, 2021 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-33771989

RESUMEN

Glioblastoma (GB) is a highly invasive type of brain cancer exhibiting poor prognosis. As such, its microenvironment plays a crucial role in its progression. Among the brain stromal cells, the microglia were shown to facilitate GB invasion and immunosuppression. However, the reciprocal mechanisms by which GB cells alter microglia/macrophages behavior are not fully understood. We propose that these mechanisms involve adhesion molecules such as the Selectins family. These proteins are involved in immune modulation and cancer immunity. We show that P-selectin mediates microglia-enhanced GB proliferation and invasion by altering microglia/macrophages activation state. We demonstrate these findings by pharmacological and molecular inhibition of P-selectin which leads to reduced tumor growth and increased survival in GB mouse models. Our work sheds light on tumor-associated microglia/macrophage function and the mechanisms by which GB cells suppress the immune system and invade the brain, paving the way to exploit P-selectin as a target for GB therapy.


Asunto(s)
Neoplasias Encefálicas/genética , Glioblastoma/genética , Macrófagos/metabolismo , Microglía/metabolismo , Selectina-P/genética , Animales , Antineoplásicos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Células Cultivadas , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Células HEK293 , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones SCID , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/genética , Neoplasias Experimentales/metabolismo , Selectina-P/antagonistas & inhibidores , Selectina-P/metabolismo , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/genética
5.
Medicine (Baltimore) ; 100(11): e24373, 2021 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-33725931

RESUMEN

RATIONALE: Brain metastasis of male breast cancer is extremely rare, and the pathological changes between the primary tumor and the metastatic brain tumor have not been reported. Herein, we report for the first time a case of male breast cancer with metastasis to the parietal lobe with subtype conversion after metastasis. PATIENT CONCERNS: we describe a 45-year-old male patient admitted for an incidentally found brain tumor after a motorcycle accident. The patient had been treated for breast cancer 5 years previously. The primary tumor was an invasive ductal carcinoma classified as pT1N1M0 with hormone receptor positivity (estrogen receptor ++, progesterone receptor +++, human epidermal growth factor receptor-type2 (HER2) +) and was treated with surgery, adjuvant chemotherapy, radiation therapy and endocrine therapy (tamoxifen). DIAGNOSES: Magnetic resonance imaging revealed a well enhanced focal solid tumor in the right parietal lobe (5.0 × 4.2 cm in size), Immunohistochemical staining revealed cerebral metastases of breast cancer with HER2 subtype conversion (estrogen receptor +++, progesterone receptor +++, HER2 -). INTERVENTIONS: The patient was successfully treated with surgery and whole brain irradiation (3 Gy × 10 fractions). OUTCOMES: There was no additional complication after the surgery and the patient transferred to oncology department for chemotherapy. 2 years later, he had gamma knife radiosurgery due to the recurred brain lesion and after that he discontinued the treatment and opted for hospice care. LESSONS: Male breast cancer with metastasis to the brain is an extremely rare condition. Although a few similar cases have been reported, subtype conversion in similar cases has not been reported. Therefore, we report this case of a male patient with brain metastasis of invasive ductal carcinoma with HER2 status conversion after metastasis.


Asunto(s)
Neoplasias Encefálicas/secundario , Neoplasias de la Mama Masculina/patología , Carcinoma Ductal de Mama/secundario , Neoplasias Encefálicas/metabolismo , Neoplasias de la Mama Masculina/metabolismo , Carcinoma Ductal de Mama/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Receptor ErbB-2/metabolismo , Receptores Estrogénicos/metabolismo , Receptores de Progesterona/metabolismo
6.
Mol Med Rep ; 23(5)2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33649841

RESUMEN

Recent studies have reported that gene amplified in squamous cell carcinoma 1 (GASC1) is involved in the progression of several types of cancer. However, whether GASC1 promotes glioma progression remains unknown. Therefore, the present study aimed to investigate the effect of GASC1 exposure on glioma tumorigenesis. The western blot demonstrated that grade III and IV glioma tissues exhibited a higher mRNA and protein expression of GASC1. Moreover, CD133+ U87 or U251 cells from magnetic cell separation exhibited a higher GASC1 expression. Invasion Transwell assay, clonogenic assay and wound healing assay have shown that GASC1 inhibition using a pharmacological inhibitor and specific short hairpin (sh)RNA suppressed the invasive, migratory and tumorsphere forming abilities of primary culture human glioma cells. Furthermore, GASC1­knockdown decreased notch receptor (Notch) responsive protein hes family bHLH transcription factor 1 (Hes1) signaling. GASC1 inhibition reduced notch receptor 1 (NOTCH1) expression, and a NOTCH1 inhibitor enhanced the effects of GASC1 inhibition on the CD133+ U87 or U251 cell tumorsphere forming ability, while NOTCH1 overexpression abrogated these effects. In addition, the GASC1 inhibitor caffeic acid and/or the NOTCH1 inhibitor DAPT (a γ­Secretase Inhibitor), efficiently suppressed the human glioma xenograft tumors. Thus, the present results demonstrated the importance of GASC1 in the progression of glioma and identified that GASC1 promotes glioma progression, at least in part, by enhancing NOTCH signaling, suggesting that GASC1/NOTCH1 signaling may be a potential therapeutic target for glioma treatment.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Histona Demetilasas con Dominio de Jumonji/metabolismo , Receptor Notch1/metabolismo , Animales , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Ácidos Cafeicos/farmacología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Diaminas/farmacología , Femenino , Regulación Neoplásica de la Expresión Génica , Glioma/tratamiento farmacológico , Glioma/genética , Humanos , Histona Demetilasas con Dominio de Jumonji/antagonistas & inhibidores , Histona Demetilasas con Dominio de Jumonji/genética , Masculino , Ratones Desnudos , Interferencia de ARN , Receptor Notch1/antagonistas & inhibidores , Receptor Notch1/genética , Transducción de Señal/genética , Tiazoles/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
7.
J Transl Med ; 19(1): 99, 2021 03 06.
Artículo en Inglés | MEDLINE | ID: mdl-33676540

RESUMEN

BACKGROUND: Glioma, the most common primary brain tumor, account Preparing figures for 30 to 40% of all intracranial tumors. Herein, we aimed to study the effects of M2 macrophage-derived exosomal microRNAs (miRNAs) on glioma cells. METHODS: First, we identified seven differentially expressed miRNAs in infiltrating macrophages and detected the expression of these seven miRNAs in M2 macrophages. We then selected hsa-miR-15a-5p (miR-15a) and hsa-miR-92a-3p (miR-92a) for follow-up studies, and confirmed that miR-15a and miR-92a were under-expressed in M2 macrophage exosomes. Subsequently, we demonstrated that M2 macrophage-derived exosomes promoted migration and invasion of glioma cells, while exosomal miR-15a and miR-92a had the opposite effects on glioma cells. Next, we performed the target gene prediction in four databases and conducted target gene validation by qRT-PCR, western blot and dual luciferase reporter gene assays. RESULTS: The results revealed that miR-15a and miR-92a were bound to CCND1 and RAP1B, respectively. Western blot assays demonstrated that interference with the expression of CCND1 or RAP1B reduced the phosphorylation level of AKT and mTOR, indicating that both CCND1 and RAP1B can activate the PI3K/AKT/mTOR signaling pathway. CONCLUSION: Collectively, these findings indicate that M2 macrophage-derived exosomal miR-15a and miR-92a inhibit cell migration and invasion of glioma cells through PI3K/AKT/mTOR signaling pathway.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Exosomas/metabolismo , Glioma/metabolismo , Macrófagos/metabolismo , MicroARNs/metabolismo , Transducción de Señal , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Movimiento Celular , Biología Computacional , Ciclina D1/metabolismo , Glioma/patología , Humanos , Microscopía Electrónica de Transmisión , Nanopartículas/química , Invasividad Neoplásica , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Células THP-1 , Serina-Treonina Quinasas TOR/metabolismo , Proteínas de Unión al GTP rap/metabolismo
8.
J Med Chem ; 64(3): 1570-1583, 2021 02 11.
Artículo en Inglés | MEDLINE | ID: mdl-33523674

RESUMEN

Androgen receptor (AR) contributes to the progression of glioblastoma (GBM), and antiandrogen agents have the potential to be used for the treatment of GBM. However, AR mutation commonly happens in GBM, which makes the antiandrogen agents less effective. Heat shock 27 kDa protein (HSP27) is a well-documented chaperone protein to stabilize ARs. Inhibition of HSP27 results in AR degradation regardless of the mutation status of ARs, which makes HSP27 a good target to abolish ARs in GBM. Compound I is a HSP27 inhibitor that significantly induces AR degradation in GBM cells via the proteasomal pathway, and it selectively inhibits AR-overexpressed GBM cell growth with IC50 values around 5 nM. The compound also significantly inhibits in vivo GBM xenograft at 20 mg/kg and does not cause toxicity to mice up to 80 mg/kg. These results suggest that targeting HSP27 to induce AR degradation in GBM is a promising and novel treatment.


Asunto(s)
Antagonistas de Andrógenos/farmacología , Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Proteínas de Choque Térmico HSP27/antagonistas & inhibidores , Receptores Androgénicos/efectos de los fármacos , Antagonistas de Andrógenos/toxicidad , Animales , Neoplasias Encefálicas/genética , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Diseño de Fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioblastoma/genética , Humanos , Ratones , Modelos Moleculares , Simulación del Acoplamiento Molecular , Mutación , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Receptores Androgénicos/genética , Bibliotecas de Moléculas Pequeñas , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto
10.
Nat Immunol ; 22(3): 336-346, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33574616

RESUMEN

The anatomic location and immunologic characteristics of brain tumors result in strong lymphocyte suppression. Consequently, conventional immunotherapies targeting CD8 T cells are ineffective against brain tumors. Tumor cells escape immunosurveillance by various mechanisms and tumor cell metabolism can affect the metabolic states and functions of tumor-infiltrating lymphocytes. Here, we discovered that brain tumor cells had a particularly high demand for oxygen, which affected γδ T cell-mediated antitumor immune responses but not those of conventional T cells. Specifically, tumor hypoxia activated the γδ T cell protein kinase A pathway at a transcriptional level, resulting in repression of the activatory receptor NKG2D. Alleviating tumor hypoxia reinvigorated NKG2D expression and the antitumor function of γδ T cells. These results reveal a hypoxia-mediated mechanism through which brain tumors and γδ T cells interact and emphasize the importance of γδ T cells for antitumor immunity against brain tumors.


Asunto(s)
Neoplasias Encefálicas/inmunología , Citotoxicidad Inmunológica , Glioblastoma/inmunología , Linfocitos Intraepiteliales/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Escape del Tumor , Microambiente Tumoral , Animales , Apoptosis , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Antígenos CD8/genética , Antígenos CD8/metabolismo , Línea Celular Tumoral , Técnicas de Cocultivo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Regulación Neoplásica de la Expresión Génica , Genes Codificadores de la Cadena delta de los Receptores de Linfocito T , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Linfocitos Intraepiteliales/metabolismo , Linfocitos Intraepiteliales/patología , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/patología , Masculino , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Noqueados , Ratones Desnudos , Subfamilia K de Receptores Similares a Lectina de Células NK/genética , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Fenotipo , Transducción de Señal , Hipoxia Tumoral
11.
Int J Mol Med ; 47(4)2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33537802

RESUMEN

Paris saponin H (PSH) is a type of steroid saponin derived from Rhizoma Paridis (RP; the rhizome of Paris). In our previous studies, saponins from RP exerted antiglioma activity in vitro. However, the effects of PSH on glioma have not been elucidated. The aim of the present study was to evaluate the effects of PSH on U251 glioblastoma cells and elucidate the possible underlying mechanism. The cells were treated with PSH at various concentrations for 48 h, and the cell viability, invasion, apoptosis and cycle progression were assessed using specific assay kits. The activation of Akt, 44/42­mitogen­activated protein kinase (MAPK) and the expression levels of A1 adenosine receptor (ARA1) and ARA3 were assessed by western blotting. The results demonstrated that PSH inhibited cell viability, migration and invasion, and induced apoptosis. Treatment of U251 cells with PSH induced the upregulation of p21 and p27, and the downregulation cyclin D1 and S­phase kinase associated protein 2 protein expression levels, which induced cell cycle arrest at the G1 phase. The results also demonstrated that PSH inhibited the expression of ARA1, and the agonist of ARA1, 2­chloro­N6­cyclopentyladenosine, reversed the effects of PSH. Hypoxia induced increases in the ARA3, hypoxia­inducible factor­1α (HIF­1α) and vascular endothelial growth factor (VEGF) protein expression levels, which were associated with the activation of the Akt and P44/42 MAPK pathways. Compared with the hypoxia group, PSH inhibited the expression levels of ARA3, HIF­1α and VEGF, as well as the phosphorylation levels of Akt and 44/42 MAPK, and repressed HIF­1α transcriptional activity. Furthermore, the results demonstrated that PSH inhibited the expression of HIF­1α by inhibiting the phosphorylation of Akt and 44/42 MAPK mediated by ARA3. Taken together, these results suggested that PSH reduced U251 cell viability via the inhibition of ARA1 and ARA3 expression, and further inhibited Akt and 44/42 MAPK phosphorylation, induced apoptosis and cell cycle arrest.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Glioma/metabolismo , Glioma/patología , Receptor de Adenosina A1/metabolismo , Receptor de Adenosina A3/metabolismo , Saponinas/farmacología , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Hipoxia de la Célula/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Fase G1/efectos de los fármacos , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Invasividad Neoplásica , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo
12.
Mol Cell ; 81(6): 1276-1291.e9, 2021 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-33539787

RESUMEN

Aberrant cell proliferation is a hallmark of cancer, including glioblastoma (GBM). Here we report that protein arginine methyltransferase (PRMT) 6 activity is required for the proliferation, stem-like properties, and tumorigenicity of glioblastoma stem cells (GSCs), a subpopulation in GBM critical for malignancy. We identified a casein kinase 2 (CK2)-PRMT6-regulator of chromatin condensation 1 (RCC1) signaling axis whose activity is an important contributor to the stem-like properties and tumor biology of GSCs. CK2 phosphorylates and stabilizes PRMT6 through deubiquitylation, which promotes PRMT6 methylation of RCC1, which in turn is required for RCC1 association with chromatin and activation of RAN. Disruption of this pathway results in defects in mitosis. EPZ020411, a specific small-molecule inhibitor for PRMT6, suppresses RCC1 arginine methylation and improves the cytotoxic activity of radiotherapy against GSC brain tumor xenografts. This study identifies a CK2α-PRMT6-RCC1 signaling axis that can be therapeutically targeted in the treatment of GBM.


Asunto(s)
Neoplasias Encefálicas , Carcinogénesis , Proteínas de Ciclo Celular , Glioblastoma , Factores de Intercambio de Guanina Nucleótido , Mitosis/efectos de la radiación , Proteínas de Neoplasias , Proteínas Nucleares , Proteína-Arginina N-Metiltransferasas , Animales , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/radioterapia , Carcinogénesis/genética , Carcinogénesis/metabolismo , Carcinogénesis/efectos de la radiación , Quinasa de la Caseína II/genética , Quinasa de la Caseína II/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Femenino , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/radioterapia , Factores de Intercambio de Guanina Nucleótido/genética , Factores de Intercambio de Guanina Nucleótido/metabolismo , Células HEK293 , Humanos , Masculino , Ratones , Mitosis/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteína-Arginina N-Metiltransferasas/genética , Proteína-Arginina N-Metiltransferasas/metabolismo , Transducción de Señal/genética , Transducción de Señal/efectos de la radiación , Ensayos Antitumor por Modelo de Xenoinjerto
13.
Mol Med Rep ; 23(4)2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33576438

RESUMEN

Malignant tumors of the central nervous system (CNS) are among the types of cancer with the poorest prognosis and glioma is the commonest primary CNS tumor. A mitochondrial DNA (mtDNA)­depleted cell line C6ρ0 was generated from C6 glioma cells after long­term exposure to ethidium bromide and 2',3'­dideoxycytidine in order to determine the effect of mtDNA damage on cell proliferation and pathological changes in glioma cells. Single cell clones were isolated and identified after 42 days of incubation. Repopulated cybrids were formed when the clonal C6ρ0 cells were fused with rat platelets and no difference was observed in their growth in a selective medium without uridine and pyruvate compared with the growth of the parent C6 cells. Disruption of mtDNA resulted in changes in mitochondrial morphology, decreased cell proliferation, reduced intracellular reactive oxygen species and intracellular ATP, along with decreased mtDNA and mitochondrial membrane potential in C6ρ0 cells compared with the C6 cells. Taken together, C6ρ0 cells without mtDNA were established for the first time and their characteristics were compared with parent cells. This C6ρ0 cell line could be used to explore the contribution of mitochondrial dysfunction and mtDNA mutations in the pathogenesis of glioma.


Asunto(s)
Neoplasias Encefálicas/genética , ADN Mitocondrial/genética , Glioma/genética , Mitocondrias/genética , Adenosina Trifosfato/metabolismo , Animales , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Proliferación Celular/genética , ADN Mitocondrial/metabolismo , Glioma/metabolismo , Glioma/patología , Espacio Intracelular/metabolismo , Potencial de la Membrana Mitocondrial/genética , Potencial de la Membrana Mitocondrial/fisiología , Mitocondrias/metabolismo , Ratas , Especies Reactivas de Oxígeno/metabolismo
14.
Nat Commun ; 12(1): 979, 2021 02 12.
Artículo en Inglés | MEDLINE | ID: mdl-33579912

RESUMEN

Glioblastoma (GBM) is a deadly cancer in which cancer stem cells (CSCs) sustain tumor growth and contribute to therapeutic resistance. Protein arginine methyltransferase 5 (PRMT5) has recently emerged as a promising target in GBM. Using two orthogonal-acting inhibitors of PRMT5 (GSK591 or LLY-283), we show that pharmacological inhibition of PRMT5 suppresses the growth of a cohort of 46 patient-derived GBM stem cell cultures, with the proneural subtype showing greater sensitivity. We show that PRMT5 inhibition causes widespread disruption of splicing across the transcriptome, particularly affecting cell cycle gene products. We identify a GBM splicing signature that correlates with the degree of response to PRMT5 inhibition. Importantly, we demonstrate that LLY-283 is brain-penetrant and significantly prolongs the survival of mice with orthotopic patient-derived xenografts. Collectively, our findings provide a rationale for the clinical development of brain penetrant PRMT5 inhibitors as treatment for GBM.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Proteína-Arginina N-Metiltransferasas/metabolismo , Animales , Apoptosis , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Ciclo Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Descubrimiento de Drogas , Epigenómica , Femenino , Regulación Neoplásica de la Expresión Génica , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/patología , Humanos , Ratones , Células Madre Neoplásicas/metabolismo , Proteína-Arginina N-Metiltransferasas/efectos de los fármacos , Proteína-Arginina N-Metiltransferasas/genética , Empalme del ARN , Ensayos Antitumor por Modelo de Xenoinjerto
15.
Nat Commun ; 12(1): 177, 2021 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-33420027

RESUMEN

Glioblastoma (GBM) is the most common type of adult malignant brain tumor, but its molecular mechanisms are not well understood. In addition, the knowledge of the disease-associated expression and function of YTHDF2 remains very limited. Here, we show that YTHDF2 overexpression clinically correlates with poor glioma patient prognosis. EGFR that is constitutively activated in the majority of GBM causes YTHDF2 overexpression through the EGFR/SRC/ERK pathway. EGFR/SRC/ERK signaling phosphorylates YTHDF2 serine39 and threonine381, thereby stabilizes YTHDF2 protein. YTHDF2 is required for GBM cell proliferation, invasion, and tumorigenesis. YTHDF2 facilitates m6A-dependent mRNA decay of LXRA and HIVEP2, which impacts the glioma patient survival. YTHDF2 promotes tumorigenesis of GBM cells, largely through the downregulation of LXRα and HIVEP2. Furthermore, YTHDF2 inhibits LXRα-dependent cholesterol homeostasis in GBM cells. Together, our findings extend the landscape of EGFR downstream circuit, uncover the function of YTHDF2 in GBM tumorigenesis, and highlight an essential role of RNA m6A methylation in cholesterol homeostasis.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Colesterol/metabolismo , Receptores ErbB/metabolismo , Glioblastoma/metabolismo , Proteínas de Unión al ARN/metabolismo , Adulto , Animales , Neoplasias Encefálicas/genética , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Transformación Celular Neoplásica/genética , Proteínas de Unión al ADN/metabolismo , Receptores ErbB/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Glioblastoma/genética , Glioma , Humanos , Receptores X del Hígado/metabolismo , Sistema de Señalización de MAP Quinasas , Masculino , Ratones , Fosforilación , Estabilidad del ARN , Proteínas de Unión al ARN/genética , Transducción de Señal , Factores de Transcripción/metabolismo , Transcriptoma
16.
Clin Adv Hematol Oncol ; 19(1): 40-50, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33493147

RESUMEN

Cases of human epidermal growth factor receptor 2 (HER2)-positive breast cancer represent approximately 15% to 20% of all breast cancers. Historically, this subtype of breast cancer was associated with an increased risk for the development of systemic and brain metastases and poor overall survival. The introduction of trastuzumab dramatically changed the outcomes of patients with HER2-positive disease, with many demonstrating outcomes similar to those of patients with luminal tumors. Currently, the first-line standard of care for patients with HER2-positive metastatic breast cancer is dual HER2 antibody therapy with pertuzumab/trastuzumab plus a taxane. After progression, the standard of care is trastuzumab emtansine (T-DM1). Although the treatment choices for patients whose disease has progressed on these agents are more limited, promising new drugs have emerged as effective options, including tucatinib and trastuzumab deruxtecan, which were recently approved by the US Food and Drug Administration. Finding the best treatment sequencing for each patient, developing reliable predictive biomarkers, and understanding the mechanisms of resistance to these drugs are necessary to maximize patient outcomes and quality of life. In this review, we analyze the management strategies for metastatic HER2-positive breast cancer, address specific situations, such as the treatment of patients with brain metastases, and discuss future directions in the treatment of this subtype.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias de la Mama/tratamiento farmacológico , Receptor ErbB-2/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/secundario , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Femenino , Humanos , Inmunoconjugados/uso terapéutico , Metástasis de la Neoplasia , Oxazoles/uso terapéutico , Piridinas/uso terapéutico , Quinazolinas/uso terapéutico , Receptor ErbB-2/genética , Taxoides/uso terapéutico , Trastuzumab/uso terapéutico
17.
Aging (Albany NY) ; 13(1): 1510-1527, 2021 01 05.
Artículo en Inglés | MEDLINE | ID: mdl-33472174

RESUMEN

Despite a growing proportion of aged individuals at risk for developing cancer in the brain, the prognosis for these conditions remains abnormally poor due to limited knowledge of underlying mechanisms and minimal treatment options. While cancer metabolism in other organs is commonly associated with upregulated glycolysis (i.e. Warburg effect) and hyperactivation of PIK3/AKT/mTOR (PAM) pathways, the unique bioenergetic demands of the central nervous system may interact with these oncogenic processes to promote tumor progression in aging. Specifically, constitutive glycolysis and PIK3/AKT/mTOR signaling in glia may be dysregulated by age-dependent alterations in neurometabolic demands, ultimately contributing to pathological processes otherwise associated with PIK3/AKT/mTOR induction (e.g. cell cycle entry, impaired autophagy, dysregulated inflammation). Although several limitations to this theoretical model exist, the consideration of aberrant PIK3/AKT/mTOR signaling in glia during aging elucidates several therapeutic opportunities for brain tumors, including non-pharmacological interventions.


Asunto(s)
Envejecimiento/metabolismo , Neoplasias Encefálicas/metabolismo , Neuroglía/metabolismo , Transducción de Señal/fisiología , Animales , Humanos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismo
18.
PLoS One ; 16(1): e0241157, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33406123

RESUMEN

We previously reported that IF7 peptide, which binds to the annexin A1 (ANXA1) N-terminus, functions as a tumor vasculature-targeted drug delivery vehicle after intravenous injection. To enhance IF7 stability in vivo, we undertook mirror-image peptide phage display using a synthetic D-peptide representing the ANXA1 N-terminus as target. We then identified peptide sequences, synthesized them as D-amino acids, and designated the resulting peptide dTIT7, which we showed bound to the ANXA1 N-terminus. Whole body imaging of mouse brain tumor models injected with near infrared fluorescent IRDye-conjugated dTIT7 showed fluorescent signals in brain and kidney. Furthermore, orally-administered dTIT7/geldanamycin (GA) conjugates suppressed brain tumor growth. Ours is a proof-of-concept experiment showing that ANXA1-binding D-peptide can be developed as an orally-administrable tumor vasculature-targeted therapeutic.


Asunto(s)
Anexina A1/antagonistas & inhibidores , Neoplasias Encefálicas/irrigación sanguínea , Neoplasias Encefálicas/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Proteínas de Neoplasias/antagonistas & inhibidores , Neovascularización Patológica/tratamiento farmacológico , Péptidos , Administración Oral , Animales , Anexina A1/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Proteínas de Neoplasias/metabolismo , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Péptidos/síntesis química , Péptidos/química , Péptidos/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto
19.
Brain ; 144(2): 636-654, 2021 03 03.
Artículo en Inglés | MEDLINE | ID: mdl-33479772

RESUMEN

As the clinical failure of glioblastoma treatment is attributed by multiple components, including myelin-associated infiltration, assessment of the molecular mechanisms underlying such process and identification of the infiltrating cells have been the primary objectives in glioblastoma research. Here, we adopted radiogenomic analysis to screen for functionally relevant genes that orchestrate the process of glioma cell infiltration through myelin and promote glioblastoma aggressiveness. The receptor of the Nogo ligand (NgR1) was selected as the top candidate through Differentially Expressed Genes (DEG) and Gene Ontology (GO) enrichment analysis. Gain and loss of function studies on NgR1 elucidated its underlying molecular importance in suppressing myelin-associated infiltration in vitro and in vivo. The migratory ability of glioblastoma cells on myelin is reversibly modulated by NgR1 during differentiation and dedifferentiation process through deubiquitinating activity of USP1, which inhibits the degradation of ID1 to downregulate NgR1 expression. Furthermore, pimozide, a well-known antipsychotic drug, upregulates NgR1 by post-translational targeting of USP1, which sensitizes glioma stem cells to myelin inhibition and suppresses myelin-associated infiltration in vivo. In primary human glioblastoma, downregulation of NgR1 expression is associated with highly infiltrative characteristics and poor survival. Together, our findings reveal that loss of NgR1 drives myelin-associated infiltration of glioblastoma and suggest that novel therapeutic strategies aimed at reactivating expression of NgR1 will improve the clinical outcome of glioblastoma patients.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Glioblastoma/metabolismo , Glioblastoma/patología , Vaina de Mielina/metabolismo , Receptor Nogo 1/metabolismo , Animales , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Proteína 1 Inhibidora de la Diferenciación/metabolismo , Proteínas Inhibidoras de la Diferenciación/metabolismo , Ratones Endogámicos BALB C , Vaina de Mielina/patología , Proteasas Ubiquitina-Específicas/metabolismo
20.
BMC Cancer ; 21(1): 83, 2021 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-33472598

RESUMEN

BACKGROUND: Non-invasive diagnosis of IDH1 mutation for gliomas has great clinical significance, and PET has natural advantage to detect metabolism, as IDH mutated gliomas share lower glucose consumption. METHODS: Clinical data of patients with gliomas and 18F-FDG PET were retrospectively reviewed. Receiver operating characteristic curve (ROC) analysis was conducted, and standard uptake value (SUV) was estimated in combination with grades or IDH1 mutation. The glucose consumption was investigated with U251 cells expressing wild-type or mutated IDH1 by glucose assay. Quantification of glucose was determined by HPLC in clinical tissues. Meanwhile, bioinformatics and western blot were applied to analyze the expression level of metabolic enzymes (e.g. HK1, PKM2, PC) in gliomas. RESULTS: Seventy-one glioma cases were enrolled, including 30 carrying IDH1 mutation. The sensitivity and specificity dependent on SUVmax (3.85) predicting IDH1 mutation reached 73.2 and 86.7%, respectively. The sensitivity and specificity of differentiating grades by SUVmax (3.1) were 92.3 and 64.4%, respectively. Glucose consumption of U251 IDH1 mutant cells (0.209 ± 0.0472 mg/ml) was obviously lower than IDH1wild-type cells (0.978 ± 0.0773 mg/ml, P = 0.0001) and astrocyte controls (0.335 ± 0.0592 mg/ml, P = 0.0451). Meanwhile, the glucose quantity in IDH1mutant glioma samples were significantly lower than those in IDH1 wild-type tissues (1.033 ± 1.19608 vs 6.361 ± 4.3909 mg/g, P = 0.0051). Silico analysis and western blot confirmed that HK1 and PKM2 in IDH1 wild-type gliomas were significantly higher than in IDH1 mutant group, while PC was significantly higher in IDH1 mutant gliomas. CONCLUSION: SUVmax on PET can predict IDH1 mutation with adequate sensitivity and specificity, as is supported by reduced glucose consumption in IDH1 mutant gliomas.


Asunto(s)
Neoplasias Encefálicas/patología , Glioma/patología , Glucosa/metabolismo , Isocitrato Deshidrogenasa/genética , Mutación , Tomografía de Emisión de Positrones/métodos , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Estudios de Casos y Controles , Fluorodesoxiglucosa F18/metabolismo , Estudios de Seguimiento , Glioma/diagnóstico por imagen , Glioma/genética , Glioma/metabolismo , Humanos , Pronóstico , Curva ROC , Radiofármacos/metabolismo , Células Tumorales Cultivadas
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