RESUMO
Glioblastoma (GBM), one of the most malignant brain tumors in the world, has limited treatment options and a dismal survival rate. Effective and safe disease-modifying drugs for glioblastoma are urgently needed. Here, we identified a small molecule, Molephantin (EM-5), effectively penetrated the blood-brain barrier (BBB) and demonstrated notable antitumor effects against GBM with good safety profiles both in vitro and in vivo. Mechanistically, EM-5 not only inhibits the proliferation and invasion of GBM cells but also induces cell apoptosis through the reactive oxygen species (ROS)-mediated PI3K/Akt/mTOR pathway. Furthermore, EM-5 causes mitochondrial dysfunction and blocks mitophagy flux by impeding the fusion of mitophagosomes with lysosomes. It is noteworthy that EM-5 does not interfere with the initiation of autophagosome formation or lysosomal function. Additionally, the mitophagy flux blockage caused by EM-5 was driven by the accumulation of intracellular ROS. In vivo, EM-5 exhibited significant efficacy in suppressing tumor growth in a xenograft model. Collectively, our findings not only identified EM-5 as a promising, effective, and safe lead compound for treating GBM but also uncovered its underlying mechanisms from the perspective of apoptosis and mitophagy.
Assuntos
Apoptose , Neoplasias Encefálicas , Proliferação de Células , Glioblastoma , Mitofagia , Espécies Reativas de Oxigênio , Ensaios Antitumorais Modelo de Xenoenxerto , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Glioblastoma/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Humanos , Mitofagia/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/metabolismo , Camundongos , Proliferação de Células/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Camundongos Nus , Serina-Treonina Quinases TOR/metabolismo , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
BACKGROUND: Atypical teratoid/rhabdoid tumor (AT/RT) is a malignant pediatric tumor of the central nervous system (CNS) with high recurrence and low survival rates that is often misdiagnosed. MicroRNAs (miRNAs) are involved in the tumorigenesis of numerous pediatric cancers, but their roles in AT/RT remain unclear. METHODS: In this study, we used miRNA sequencing and gene expression microarrays from patient tissue to study both the miRNAome and transcriptome traits of AT/RT. RESULTS: Our findings demonstrate that 5 miRNAs were up-regulated, 16 miRNAs were down-regulated, 179 mRNAs were up-regulated and 402 mRNAs were down-regulated in AT/RT. qPCR revealed that hsa-miR-17-5p and MAP7 mRNA were the most significantly differentially expressed miRNA and mRNA in AT/RT tissues. Furthermore, the results from analyses using the miRTarBase database identified MAP7 mRNA as a target gene of hsa-miR-17-5p. CONCLUSIONS: Our findings suggest that the dysregulation of hsa-miR-17-5p may be a pivotal event in AT/RT and miRNAs that may represent potential therapeutic targets and diagnostic biomarkers.
Assuntos
Neoplasias do Sistema Nervoso Central , MicroRNAs , Tumor Rabdoide , Neoplasias do Sistema Nervoso Central/genética , Criança , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Mensageiro/genética , Tumor Rabdoide/genéticaRESUMO
Glioblastoma (GBM) is the most malignant primary brain tumor in adults. Due to its invasive nature, it cannot be thoroughly eliminated. WD repeat domain 12 (WDR12) processes the 32S precursor rRNA but cannot affect the synthesis of the 45S/47S primary transcript. In this study, we found that WDR12 is highly expressed in GBM according to the analysis results of mRNA expression by The Cancer Genome Atlas database. The high expression level of WDR12 is dramatically related to shorter overall survival and reduced disease-free survival. Next, we knocked down WDR12 and found that knockdown of WDR12 promoted the apoptosis and inhibited the proliferation by cell biology experiments. Differential expression genes in gene-chip revealed that WDR12 knockdown mainly inhibited cell cycle. Finally, we also found that WDR12 is associated with PLK1 and EZH2 in cell proliferation of GBM. Resumptively, this report showed a possible evidence that WDR12 drove malignant behavior of GBM, whose expression may present a neoteric independent prognostic biomarker in GBM.
Assuntos
Neoplasias Encefálicas/genética , Proteínas de Ciclo Celular/genética , Regulação Neoplásica da Expressão Gênica/genética , Glioblastoma/genética , Oncogenes/genética , Proteínas de Ligação a RNA/genética , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Genômica/métodos , Glioblastoma/patologia , Humanos , Prognóstico , RNA Mensageiro/genéticaRESUMO
Blue rubber bleb nevus syndrome (BRBNS) is a rare vascular anomaly syndrome consisting of multifocal venous malformations (VM). The malformations are most. prominent in the skin, soft tissues and gastrointestinal (GI) tract. Chronic bleeding induced by the vascular malformation (VM) lesions in gastrointestinal (GI) tract was the main clinical problem which should be treated. In this paper, two patients with BRBNS were treated by surgery for gastrointestinal bleeding. Our results indicated the endoscope examination was the best diagnostic way for VM in GI. Although many therapeutic methods have been tried, aggressive surgical eradication was the most effective for venous anomalies that cause GI bleeding in BRBNS.
