RESUMO
Chronic oxidative stress resulting from hyperlipidemia is thought to be a key pathogenic driver of pancreatic ß-cell dysfunction in leading to the onset of type 2 diabetes mellitus (T2DM). Long non-coding RNAs (lncRNAs) have been increasingly recognized to regulate dysfunction within pancreatic ß-cells in the context of T2DM. In the present study, we sought to comprehensively analyze the roles of lncRNAs in dysfunctional ß-cells and mouse islets. Analyses of INS-1E cells were performed by RNA-seq and qRT-PCR after treating with or without 0.5 mM palmitate for 4 days, leading us to identify the novel lncRNA Eif4g2 (lncEif4g2) as a functional regulator within these cells. When we overexpressed lncEif4g2 in INS-1E ß-cells and mouse islets, this was sufficient for the reversal of palmitate-mediated reductions in cell viability, insulin production, ATP production by mitochondria, and creation of intracellular reactive oxygen species (ROS) and the dysfunction of mouse islets, with nuclear factor erythroid 2 related factor 2 (Nrf2) activation also being observed. In contrast, when lncEif4g2 was knocked down this led INS-1E cells and mouse islets to become more sensitive to palmitate-induced dysfunction, with reduced Nrf2 nuclear translocation also being detected. When antioxidants were used to treat INS-1E cells and mouse islets, however, these negative effects were reversed. Additional functional analyses revealed lncEif4g2 to be capable of directly binding to miR-3074-5p in ß-cells, with the expression of lncEif4g2 and miR-3074-5p being negatively correlated with one another. We further found that cAMP-responsive element binding-protein (CREB) was a miR-3074-5p target gene in these cells, thus at least in part serving as a functional mediator of the lncEif4g2/miR-3074-5p axis within dysfunctional ß-cells. In summary, our results thus reveal that lncEif4g2 is able to indirectly regulate the expression of CREB via targeting miR-3074-5p in INS-1E cells and mouse islets, thereby leading to enhanced Nrf2 activation.
Assuntos
Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Ácido Palmítico/toxicidade , RNA Longo não Codificante/metabolismo , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Sequência de Bases , Linhagem Celular , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Células Secretoras de Insulina/efeitos dos fármacos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , Estresse Oxidativo/efeitos dos fármacos , RNA Longo não Codificante/genéticaRESUMO
Glioma cells rely on glycolysis to obtain energy and sustain their survival under microenvironmental stress in vivo. The mechanisms of regulation of glycolysis in glioma cells are unclear. Signaling pathway mediated by the transcription factor X box-binding protein 1 (XBP1) is one of the most important pathways of unfolded protein response which is comprehensively activated in cancer cells upon the microenvironmental stress. Here we showed that XBP1 was significantly activated in glioma tissues in vivo. XBP1 silencing resulted in decreasing of glioma cell viability and ATP/lactate production under hypoxia, which is possibly mediated by inhibition of Hexokinase II (HK2)'s expression. More importantly, XBP1 silenced glioma cells showed the decrease of tumor formation capacity. Our results revealed that XBP1s activation was involved in glioma glycolysis regulation and might be a potential molecular target for glioma treatment.
Assuntos
Apoptose , Proteínas de Ligação a DNA/antagonistas & inibidores , Inativação Gênica , Glicólise , Hexoquinase/antagonistas & inibidores , RNA Interferente Pequeno/genética , Fatores de Transcrição/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Animais , Proliferação de Células , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Glioma , Hexoquinase/genética , Hexoquinase/metabolismo , Humanos , Hipóxia/fisiopatologia , Ácido Láctico/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Consumo de Oxigênio , Ratos Wistar , Fatores de Transcrição de Fator Regulador X , Transdução de Sinais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Células Tumorais Cultivadas , Proteína 1 de Ligação a X-Box , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND/AIMS: Glioblastoma multiforme (GBM) is the most malignant primary brain tumor with a poor prognosis. Combination treatment of autophagy inducer and autophagy inhibitor may be a feasible solution to improve the therapeutic effects. However, the correlation between them is unclear. The purpose of this study was to investigate the effect of autophagy inhibition at different stages on cytotoxicity of autophagy inducers in glioblastoma cells. METHODS: Autophagy inhibition at early stage was achieved by 3-methyladenine (3-MA) or Beclin 1 shRNA. Autophagy inhibition at late stage was achieved by chloroquine (CQ) or Rab7 shRNA. Cell viability was assessed by MTT assay. Autophagy was measured using transmission electron microscopy and western blot. Apoptosis was measured using western blot and flow-cytometry. RESULTS: Inhibition of early steps of autophagy by 3-MA or Beclin 1 knockdown decreased the toxic effect of arsenic trioxide (ATO) in GBM cell lines. In contrast, blockade of autophagy flux at late stage by CQ or Rab7 knockdown enhanced the cytotoxicity of ATO, and caused accumulation of degradative autophagic vacuoles and robust apoptosis. Moreover, depletion of Beclin 1 abolished the synergistic effect of ATO and CQ by reducing autophagy and apoptosis. Combination of CQ with other autophagy inducers also induced synergistic apoptotic cell death. CONCLUSION: These results suggest that inhibition of late process of autophagy, not initial step, increases the cytotoxic effect of autophagy inducers via autophagy and apoptosis, which may contribute to GBM chemotherapy.
Assuntos
Adenina/análogos & derivados , Antineoplásicos/farmacologia , Arsenicais/farmacologia , Autofagia/efeitos dos fármacos , Óxidos/farmacologia , Adenina/farmacologia , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Trióxido de Arsênio , Proteína Beclina-1 , Western Blotting , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Cloroquina/farmacologia , Sinergismo Farmacológico , Citometria de Fluxo , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Microscopia Eletrônica de Transmissão , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Proteínas rab de Ligação ao GTP/antagonistas & inibidores , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismo , proteínas de unión al GTP Rab7RESUMO
Shale gas extraction process generates a large amount of shale gas flowback wastewater (SGFW) containing refractory organic compounds, which can pose serious environmental threats if not properly treated. However, the extremely complex compositions of organics in SGFW are still unknown and their transformation pathways in O3- and â¢OH-dominated systems are not well recognized, which restrain the selection of treatment technology and optimization of operational parameters. The removal characteristics and reaction mechanism of dissolved organic matter (DOM) in SGFW treated by ozonation and Fenton processes were comparatively investigated using electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry. The results showed that both processes could degrade low-oxygen highly unsaturated and phenolic organics, polyphenolics and polycyclic aromatics, and transform them into aliphatic organics and high-oxygen highly unsaturated and phenolic organics. With increasing action of reactive oxygen species (O3 for ozonation and â¢OH for Fenton process), the degradation products (mainly aliphatic organics) increased during ozonation. However, in Fenton process, a wider range of DOM was removed without aliphatic organics accumulation. The degradation mechanisms of DOM during ozonation and Fenton processes included oxygen addition reactions (+3O, +H2O2, and +2O) as dominant pathways. However, ozonation showed more violent oxygenation, hydroxylation, and carboxylation, while Fenton process presented more violent chain-breaking reactions. These results revealed the selective oxidation of ozone and nonselective oxidation of â¢OH during SGFW treatment, and provided theoretical support for selecting SGFW treatment approaches.
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The cementitious material based on phosphogypsum (PG) and ground granulated blast furnace slag (GBFS) demonstrates good economy and sustainability, whereas its drawback of ultra-slow strength development seems unacceptable. In this study, an attempt to drive the hydration of PG-GBFS and further facilitate the strength development by introducing nano-ettringite (NE) was carried out. The impact of 1- 5 % NE on the compressive strength, hydration process, dissolution behavior, and microstructure evolution of PG-GBFS were investigated. The results showed that the incorporation of NE significantly increased the compressive strength of PG-GBFS. At 7 d, the strength grew from 0 MPa to a range of 7.6- 20.2 MPa, and at 28 d, it was enhanced from 22.9 MPa to a range of 45.6- 79.0 MPa. The reason was that the introduction of NE induced the formation of AFt, thereby accelerating the hydration process and promoting the development of the skeletal network, resulting in higher early strength. Besides, NE facilitated the formation of C-S(A)-H gel, which further refined the pore structure and led to continuous growth in later strength. Additionally, PG-GFBS with 5 % NE exhibited significantly lower total costs (35.0 % of NaOH-activated slag and 51.7 % of water glass-activated slag) and lower carbon emissions (30.8 % of NaOH-activated slag and 49.8 % of water glass-activated slag) at the same 28 d compressive strength, indicating its strong competitiveness in both sustainability and economy.
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Pathological angiogenesis is a critical contributor to atherosclerotic plaque rupture. However, there are few effective theranostic strategies to stabilize plaques by suppressing neovascularization. In this study, we fabricated a polymeric nanosystem using 3 nm manganese ferrite (MnFe2O4) and perfluorohexane (PFH) stabilized by polylactic acid-glycolic acid (PLGA) shells and conjugated to the surface of an anti-vascular endothelial growth factor receptor 2 (VEGFR2) antibody [ramucirumab (Ram)]. The PFH@PLGA/MnFe2O4-Ram nanoparticles (NPs) were used as atherosclerotic plaque angiogenesis theranostics for multimodal imaging-guided photothermal therapy (PTT). Three-nanometer MnFe2O4 is an excellent magnetic resonance imaging T1 and photoacoustic imaging contrast agent. Upon exposure to near-infrared (NIR) light, MnFe2O4 in the NPs could transform NIR light into thermal energy for the photothermal elimination of plaque angiogenesis. Additionally, optical droplet vaporization of PFH in the NPs triggered by the thermal effect to form gas bubbles enhanced ultrasound imaging. Our in vitro experiments revealed that PFH@PLGA/MnFe2O4-Ram NPs actively accumulated in rabbit aortic endothelial cells, and NP-mediated PTT promoted endothelial cell apoptosis while inhibiting their proliferation, migration, and tubulogenesis. Notably, the PFH@PLGA/MnFe2O4-Ram NPs possessed excellent photostability and biocompatibility. In the rabbit advanced atherosclerotic plaque model, PFH@PLGA/MnFe2O4-Ram NP-guided PTT significantly induced apoptosis of neovascular endothelial cells and improved the hypoxia status in the plaque 3 days after treatment. On day 28, PTT significantly reduced the density of neovessels and subsequently stabilized rabbit plaques by inhibiting plaque hemorrhage and macrophage infiltration. Collectively, these results suggest that PFH@PLGA/MnFe2O4-Ram NP-guided PTT is a safe and effective theranostic strategy for inhibiting atherosclerotic plaque angiogenesis.
Assuntos
Nanopartículas , Placa Aterosclerótica , Animais , Linhagem Celular Tumoral , Células Endoteliais , Compostos Férricos , Imagem Multimodal , Neovascularização Patológica/diagnóstico por imagem , Neovascularização Patológica/tratamento farmacológico , Fototerapia , Placa Aterosclerótica/diagnóstico por imagem , Coelhos , Nanomedicina TeranósticaRESUMO
Pathological angiogenesis is a crucial factor that causes atherosclerotic plaque rupture. Sinoporphyrin sodium-mediated sonodynamic therapy (DVDMS-SDT) induces regression of plaque neovascularization in humans without causing obvious side effects. However, a clinical noninvasive theranostic strategy for atherosclerotic plaque neovascularization is urgently needed. A nanoplatform designed for multimodality imaging-guided SDT in plaque angiogenesis theranostics, termed PFP-HMME@PLGA/MnFe2 O4 -ramucirumab nanoparticles (PHPMR NPs), is fabricated. It encapsulates manganese ferrite (MnFe2 O4 ), hematoporphyrin monomethyl ether (HMME), and perfluoropentane (PFP) stabilized by polylactic acid-glycolic acid (PLGA) shells and is conjugated to an anti-VEGFR-2 antibody. With excellent magnetic resonance imaging (MRI)/photoacoustic/ultrasound imaging ability, the distribution of PHPMR NPs in plaque can be observed in real time. Additionally, they actively accumulate in the mitochondria of rabbit aortic endothelial cells (RAECs), and the PHPMR NP-mediated SDT promotes mitochondrial-caspase apoptosis via the production of reactive oxygen species and inhibits the proliferation, migration, and tubulogenesis of RAECs. On day 3, PHPMR NP-mediated SDT induces apoptosis in neovessel endothelial cells and improves hypoxia in the rabbit advanced plaque. On day 28, PHPMR NP-mediated SDT reduces the density of neovessels, subsequently inhibiting intraplaque hemorrhage and inflammation and eventually stabilizing the plaque. Collectively, PHPMR NP-mediated SDT presents a safe and effective theranostic strategy for inhibiting plaque angiogenesis.
Assuntos
Compostos Férricos/administração & dosagem , Compostos de Manganês/administração & dosagem , Neovascularização Patológica/complicações , Neovascularização Patológica/terapia , Placa Aterosclerótica/complicações , Placa Aterosclerótica/terapia , Nanomedicina Teranóstica/métodos , Terapia por Ultrassom/métodos , Animais , Modelos Animais de Doenças , Masculino , Nanopartículas , Neovascularização Patológica/patologia , Placa Aterosclerótica/patologia , CoelhosRESUMO
Background: Neoadjuvant chemotherapy is relevant to the formation of thromboembolism and secondary neoplasms in triple-negative breast cancer (TNBC). Chemotherapy-induced breast cancer cell-derived microparticles (BCMPs) may have important thrombogenic and pro-metastatic effects on platelets and endothelium, which may be related to the expression and distribution of phosphatidylserine (PS). However, investigating these interactions is challenging due to technical limitations. Methods: A study was conducted in 20 healthy individuals and 18 patients who had been recently diagnosed with TNBC and were undergoing neoadjuvant chemotherapy with doxorubicin and cyclophosphamide. BCMPs were isolated from patient blood samples and doxorubicin-treated breast cancer cell lines. Their structure and morphology were studied by electron microscopy and antigen levels were measured by fluorescence-activated cell sorting. In an inhibition assay, isolated BCMPs were pretreated with lactadherin or tissue factor antibodies. Platelets isolated from healthy subjects were treated with BCMPs and coagulation time, fibrin formation, and expression of intrinsic/extrinsic factor Xase (FXa) and thrombin were evaluated. The effects of BCMPs on endothelial thrombogenicity and integrity were assessed by confocal microscopy, electron microscopy, measurement of intrinsic/extrinsic FXa, prothrombinase assay, and transwell permeability assay. Results: Neoadjuvant chemotherapy significantly increased the expression of PS+ BCMPs in patient plasma. Its expression was associated with a rapid increase in procoagulant activity. Treatment with lactadherin, a PS-binding scavenging molecule, markedly reduced the adhesion of BCMPs and abolished their procoagulant activity, but this was not observed with tissue factor antibody treatment. Intravenous injection of BCMPs in mice induced a significant hypercoagulable state, reducing the extent of plasma fibrinogen and promoting the appearance of new thrombus. Cancer cells incubated with doxorubicin released large numbers of PS+ BCMPs, which stimulated and transformed endothelial cells into a procoagulant phenotype and increased the aggregation and activation of platelets. Moreover, cancer cells exploited this BCMP-induced endothelial leakiness and showed promoted metastasis. Pretreatment with lactadherin increased uptake of both PS+ BCMPs and cancer cells by endothelial cells and limited the transendothelial migration of cancer cells. Conclusion: Lactadherin, a biosensor that we developed, was used to study the extracellular vesicle distribution of PS, which revealed a novel PS+ BCMPs administrative axis that initiated a local coagulation cascade and facilitated metastatic colonization of circulating cancer cells.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Micropartículas Derivadas de Células/fisiologia , Lipídeos de Membrana/análise , Terapia Neoadjuvante/efeitos adversos , Fosfatidilserinas/análise , Trombofilia/etiologia , Migração Transendotelial e Transepitelial , Neoplasias de Mama Triplo Negativas/patologia , Idoso , Animais , Anticorpos/imunologia , Antígenos de Superfície/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fatores de Coagulação Sanguínea/análise , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Endotélio Vascular/patologia , Feminino , Fibrinólise , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Proteínas do Leite/farmacologia , Tromboplastina/imunologia , Neoplasias de Mama Triplo Negativas/sangue , Neoplasias de Mama Triplo Negativas/tratamento farmacológicoRESUMO
Breast cancer (BRCA) is a highly heterogeneous disease due to the complicated microenvironment in the tumor, making the treatment benefits varied. Therefore, this study aims to identify a gene signature in the tumor microenvironment (TME) associated with the prognosis of BRCA patients. We downloaded the immune, stromal, and proliferation (ISP)-associated genes from the literature on BRCA. mRNA expression and clinical information obtained from The Cancer Genome Atlas (TCGA) were performed to identify the initial biomarker. Furthermore, we validated the robustness of the gene signature in the independent validation data set GSE20685. A four-gene signature in TME, including CD74, MMP9, RPA3, and SHCBP1, was constructed to predict the overall survival of BRCA. The survival time of the high-risk group was significantly worse than that of the low-risk group. Univariate and multivariate Cox regression analysis showed that our four-gene ISP signature was an independent prognostic factor in TCGA and GSE20685 data sets. The AUC suggested that our four-gene ISP signature was comparable to TNM classification at predicting the overall survival of BRCA patients. Interestingly, BRCA patients with high-risk scores were more likely to be associated with stromal and proliferation of cancer. In contrast, those with high-risk scores were more likely to be associated with tumor immunity-related pathway. We found an innovative biomarker in TME to predict the prognosis of BRCA. This signal might reflect the imbalance of TME and provide potential biomarkers for the individualized and precise treatment of BRCA.
Assuntos
Neoplasias da Mama/genética , Microambiente Tumoral/genética , Adulto , Antígenos CD/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/metabolismo , Proteínas de Ligação a DNA/genética , Bases de Dados Genéticas , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Haplótipos/genética , Humanos , Metaloproteinase 9 da Matriz/genética , Pessoa de Meia-Idade , Prognóstico , RNA Longo não Codificante/genética , Fatores de Risco , Proteínas Adaptadoras da Sinalização Shc/genética , Sialiltransferases/genéticaRESUMO
Tumor microenvironment (TME) plays an essential role in the development and metastasis of breast cancer (BC). More studies are needed on the differences and functions of immune components and matrix components. In this study, we calculated the proportion of tumor-infiltrating immune cells (TICs) and the proportion of immune and matrix components of BC patients from The Cancer Genome Atlas (TCGA). We performed Cox regression analysis and constructed protein-protein interaction (PPI) network based on the differentially expressed genes (DEGs) and obtained the most crucial gene CD52. CD52 significantly upregulated and affected the prognosis of BC patients. Gene set enrichment analysis (GSEA) suggested that the genes in the CD52 high-expression group were mainly enriched in immune-related pathways, while those in the CD52 low-expression group were mainly enriched in metabolic pathways. TICs analyses showed that there should be a positive correlation between CD52 expression and CD8+ T cells, activated memory CD4+ T cells, macrophage M1, and Gamma Delta T cells. It indicated that CD52 might be an essential factor in maintaining the immune-dominant position of TME. These results suggest that CD52 might be a potential biomarker for prognosis and provide a new therapeutic target for BC patients.
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During atherosclerosis plaque progression, pathological intraplaque angiogenesis leads to plaque rupture accompanied by thrombosis, which is probably the most important cause of arteries complications such as cerebral and myocardial infarction. Even though few treatments are available to mitigate plaque rupture, further investigation is required to develop a robust optimized therapeutic method. In this study using rabbit and mouse atherosclerotic models, sinoporphyrin sodium (DVDMS)-mediated sonodynamic therapy reduced abnormal angiogenesis and plaque rupture. Briefly, DVDMS is injected to animals, and then the plaque was locally exposed to pulse ultrasound for a few minutes. Furthermore, a small size clinical trial was conducted on patients with atherosclerosis. Notably, a significant reduction of arterial inflammation and angiogenesis was recorded following a short period of DVDMS-mediated sonodynamic therapy treatment. This beneficial outcome was almost equivalent to the therapeutic outcome after 3-month intensive statin treatment.
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As breast cancer tissues are stiffer than normal tissues, shear wave elastography (SWE) can locally quantify tissue stiffness and provide histological information. Moreover, tissue stiffness can be observed on three-dimensional (3D) colour-coded elasticity maps. Our objective was to evaluate the diagnostic performances of quantitative features in differentiating breast masses by two-dimensional (2D) and 3D SWE. Two hundred ten consecutive women with 210 breast masses were examined with B-mode ultrasound (US) and SWE. Quantitative features of 3D and 2D SWE were assessed, including elastic modulus standard deviation (ESDE) measured on SWE mode images and ESDU measured on B-mode images, as well as maximum elasticity (Emax). Adding quantitative features to B-mode US improved the diagnostic performance (p < 0.05) and reduced false-positive biopsies (p < 0.0001). The area under the receiver operating characteristic curve (AUC) of 3D SWE was similar to that of 2D SWE for ESDE (p = 0.026) and ESDU (p = 0.159) but inferior to that of 2D SWE for Emax (p = 0.002). Compared with ESDU, ESDE showed a higher AUC on 2D (p = 0.0038) and 3D SWE (p = 0.0057). Our study indicates that quantitative features of 3D and 2D SWE can significantly improve the diagnostic performance of B-mode US, especially 3D SWE ESDE, which shows considerable clinical value.
Assuntos
Neoplasias da Mama/diagnóstico por imagem , Mama/diagnóstico por imagem , Técnicas de Imagem por Elasticidade/métodos , Ultrassonografia Mamária/métodos , Adulto , Mama/patologia , Neoplasias da Mama/patologia , Módulo de Elasticidade , Feminino , Humanos , Pessoa de Meia-Idade , Curva ROC , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
Glioma relies on glycolysis to obtain energy and sustain its survival under low glucose microenvironment in vivo. The mechanisms on glioma cell glycolysis regulation are still unclear. Signaling mediated by Double-stranded RNA-activated protein kinase (PKR) - like ER kinase (PERK) is one of the important pathways of unfolded protein response (UPR) which is comprehensively activated in cancer cells upon the hypoxic and low glucose stress. Here we show that PERK is significantly activated in human glioma tissues. PERK silencing results in decreased glioma cell viability and ATP/lactate production upon low glucose stress, which is mediated by partially blocked AKT activation and subsequent inhibition of Hexokinase II (HK2)'s mitochondria translocation. More importantly, PERK silenced glioma cells show decreased tumor formation capacity. Our results reveal that PERK activation is involved in glioma glycolysis regulation and may be a potential molecular target for glioma treatment.