RESUMO
The different cell types in the brain have highly specialized roles with unique metabolic requirements. Normal brain function requires the coordinated partitioning of metabolic pathways between these cells, such as in the neuron-astrocyte glutamate-glutamine cycle. An emerging theme in glioblastoma (GBM) biology is that malignant cells integrate into or "hijack" brain metabolism, co-opting neurons and glia for the supply of nutrients and recycling of waste products. Moreover, GBM cells communicate via signaling metabolites in the tumor microenvironment to promote tumor growth and induce immune suppression. Recent findings in this field point toward new therapeutic strategies to target the metabolic exchange processes that fuel tumorigenesis and suppress the anticancer immune response in GBM. Here, we provide an overview of the intercellular division of metabolic labor that occurs in both the normal brain and the GBM tumor microenvironment and then discuss the implications of these interactions for GBM therapy.
Assuntos
Glioblastoma , Humanos , Encéfalo , Neuroglia , Astrócitos , Neurônios , Microambiente TumoralRESUMO
Glucose and amino acid metabolism are critical for glioblastoma (GBM) growth, but little is known about the specific metabolic alterations in GBM that are targetable with FDA-approved compounds. To investigate tumor metabolism signatures unique to GBM, we interrogated The Cancer Genome Atlas for alterations in glucose and amino acid signatures in GBM relative to other human cancers and found that GBM exhibits the highest levels of cysteine and methionine pathway gene expression of 32 human cancers. Treatment of patient-derived GBM cells with the FDA-approved single cysteine compound N-acetylcysteine (NAC) reduced GBM cell growth and mitochondrial oxygen consumption, which was worsened by glucose starvation. Normal brain cells and other cancer cells showed no response to NAC. Mechanistic experiments revealed that cysteine compounds induce rapid mitochondrial H2O2 production and reductive stress in GBM cells, an effect blocked by oxidized glutathione, thioredoxin, and redox enzyme overexpression. From analysis of the clinical proteomic tumor analysis consortium (CPTAC) database, we found that GBM cells exhibit lower expression of mitochondrial redox enzymes than four other cancers whose proteomic data are available in CPTAC. Knockdown of mitochondrial thioredoxin-2 in lung cancer cells induced NAC susceptibility, indicating the importance of mitochondrial redox enzyme expression in mitigating reductive stress. Intraperitoneal treatment of mice bearing orthotopic GBM xenografts with a two-cysteine peptide induced H2O2 in brain tumors in vivo. These findings indicate that GBM is uniquely susceptible to NAC-driven reductive stress and could synergize with glucose-lowering treatments for GBM.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Camundongos , Animais , Peróxido de Hidrogênio , Peróxidos , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , Proteômica , Acetilcisteína/farmacologia , Glucose , Linhagem Celular Tumoral , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genéticaRESUMO
PURPOSE: Physician-scientists play a crucial role in advancing biomedical sciences. Proportionally fewer physicians are actively engaged in scientific pursuits, attributed to attrition in the training and retention pipeline. This national study evaluated the ongoing and longer-term impact of the COVID-19 pandemic on stress levels, research productivity, and optimism for physician-scientists at all levels of training. METHODS: A multi-institutional cross-sectional survey of medical students, graduate students, and residents/fellows/junior faculty (RFJF) was conducted from April to August 2021 to assess the impact of COVID-19 on individual stress, productivity, and optimism. Multivariate regression analyses were performed to identify associated variables and unsupervised variable clustering techniques were employed to identify highly correlated responses. RESULTS: A total 677 respondents completed the survey, representing different stages of physician-scientist training. Respondents report high levels of stress (medical students: 85%, graduate students: 63%, RFJF: 85%) attributed to impaired productivity concerns, concern about health of family and friends, impact on personal health and impairment in training or career development. Many cited impaired productivity (medical students: 65% graduate students: 79%, RFJF: 78%) associated with pandemic impacts on training, labs closures and loss of facility/resource access, and social isolation. Optimism levels were low (medical students: 37%, graduate students: 38% and RFJF: 39%) with females less likely to be optimistic and more likely to report concerns of long-term effects of COVID-19. Optimism about the future was correlated with not worrying about the long-term effects of COVID-19. Since the COVID-19 pandemic, all respondents reported increased prioritization of time with family/friends (67%) and personal health (62%) over career (25%) and research (24%). CONCLUSIONS: This national survey highlights the significant and protracted impact of the COVID-19 pandemic on stress levels, productivity, and optimism among physician-scientists and trainees. These findings underscore the urgent need for tailored support, including mental health, academic, and career development assistance for this biomedical workforce.
Assuntos
Pesquisa Biomédica , COVID-19 , Estudantes de Medicina , Humanos , COVID-19/epidemiologia , Estudos Transversais , Feminino , Masculino , Estudantes de Medicina/psicologia , Adulto , Pandemias , Docentes de Medicina/psicologia , Inquéritos e Questionários , Estresse Psicológico/epidemiologia , Pesquisadores/psicologia , Pesquisadores/educação , SARS-CoV-2 , Otimismo , Médicos/psicologiaRESUMO
Background: Stroke is a leading cause of severe disability in the United States, but there is no effective method for patients to accurately detect the signs of stroke at home. We developed a mobile app, Destroke, that allows remote performance of a modified NIH stroke scale (NIHSS) by patients. Aims: To assess the feasibility of a mobile app for stroke monitoring and education by patients with a history of stroke. Materials and methods: We enrolled 25 patients with a history of stroke in a prospective open-label study to evaluate the feasibility of the Destroke app in patients with stroke. Nineteen patients completed all study assessments, with a median time from stroke onset to enrollment of 5.6 years (range 0.1-12 years). We designed a modified NIHSS that assessed 12 out of 16 tasks on the NIHSS. Patients completed this test eight times over a 28-day period. We conducted pre-study surveys that assessed demographic information, stroke and cardiovascular history, baseline NIHSS, and experience using mobile technologies, and mid- and post-study surveys that assessed patient satisfaction on app usage and confidence in stroke detection. Results: Ten men and nine women participated in this study (median age of 64 (33-76)), representing ten US states and Washington D.C. Median baseline NIHSS was 0 (0-4). 15 patients reported using health apps. On a 5-point Likert scale, patients rated the app as 4.2 on being able to understand and use the app and 4.3 on using the app when instructed by their doctor. For eight patients with poor confidence in detecting the signs of a stroke before the study, six showed higher confidence after the study. Conclusions: The use of an at-home stroke monitoring app is feasible by patients with a history of stroke and improves confidence in detecting the signs of stroke.
RESUMO
Purpose: Physician-scientists play a crucial role in advancing biomedical sciences. Proportionally fewer physicians are actively engaged in scientific pursuits, attributed to attrition in the training and retention pipeline. This national study evaluated the ongoing and longer-term impact of the COVID-19 pandemic on research productivity for physician-scientists at all levels of training. Methods: A survey of medical students, graduate students, and residents/fellows/junior faculty (RFJF) was conducted from April to August 2021 to assess the impact of COVID-19 on individual stress, productivity, and optimism. Multivariate regression analyses were performed to identify associated variables and unsupervised variable clustering techniques were employed to identify highly correlated responses. Results: A total 677 respondents completed the survey, representing different stages of physician-scientist training. Respondents report high levels of stress (medical students: 85%, graduate students: 63%, RFJF: 85%) attributed to impaired productivity concerns, concern about health of family and friends, impact on personal health and impairment in training or career development. Many cited impaired productivity (medical students: 65% graduate students: 79%, RFJF: 78%) associated with pandemic impacts on training, labs closures and loss of facility/resource access, and social isolation. Optimism levels were low (medical students: 37%, graduate students: 38% and RFJF: 39%) with females less likely to be optimistic and more likely to report concerns of long-term effects of COVID-19. Optimism about the future was correlated with not worrying about the long-term effects of COVID-19. Since the COVID-19 pandemic, all respondents reported increased prioritization of time with family/friends (67%) and personal health (62%) over career (25%) and research (24%). Conclusions: This national survey highlights the significant and protracted impact of the COVID-19 pandemic on stress levels, productivity, and optimism among physician-scientists and trainees. These findings underscore the urgent need for tailored support, including mental health, academic, and career development assistance for this biomedical workforce.
RESUMO
BACKGROUND: Insulin feedback is a critical mechanism responsible for the poor clinical efficacy of phosphatidylinositol 3-kinase (PI3K) inhibition in cancer, and hyperglycemia is an independent factor associated with poor prognosis in glioblastoma (GBM). We investigated combination anti-hyperglycemic therapy in a mouse model of GBM and evaluated the association of glycemic control in clinical trial data from patients with GBM. METHODS: The effect of the anti-hyperglycemic regimens, metformin and the ketogenic diet, was evaluated in combination with PI3K inhibition in patient-derived GBM cells and in an orthotopic GBM mouse model. Insulin feedback and the immune microenvironment were retrospectively evaluated in blood and tumor tissue from a Phase 2 clinical trial of buparlisib in patients with recurrent GBM. RESULTS: We found that PI3K inhibition induces hyperglycemia and hyperinsulinemia in mice and that combining metformin with PI3K inhibition improves the treatment efficacy in an orthotopic GBM xenograft model. Through examination of clinical trial data, we found that hyperglycemia was an independent factor associated with poor progression-free survival in patients with GBM. We also found that PI3K inhibition increased insulin receptor activation and T-cell and microglia abundance in tumor tissue from these patients. CONCLUSION: Reducing insulin feedback improves the efficacy of PI3K inhibition in GBM in mice, and hyperglycemia worsens progression-free survival in patients with GBM treated with PI3K inhibition. These findings indicate that hyperglycemia is a critical resistance mechanism associated with PI3K inhibition in GBM and that anti-hyperglycemic therapy may enhance PI3K inhibitor efficacy in GBM patients.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Hiperglicemia , Metformina , Humanos , Animais , Camundongos , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Fosfatidilinositol 3-Quinase/farmacologia , Fosfatidilinositol 3-Quinase/uso terapêutico , Fosfatidilinositol 3-Quinases , Insulina/farmacologia , Insulina/uso terapêutico , Retroalimentação , Estudos Retrospectivos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Proliferação de Células , Hiperglicemia/tratamento farmacológico , Metformina/farmacologia , Metformina/uso terapêutico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
PURPOSE: Physician-scientists have long been considered an endangered species, and their extended training pathway is vulnerable to disruptions. This study investigated the effects of COVID-19-related challenges on the personal lives, career activities, stress levels, and research productivity of physician-scientist trainees and faculty. METHOD: The authors surveyed medical students (MS), graduate students (GS), residents/fellows (R/F), and faculty (F) using a tool distributed to 120 U.S. institutions with MD-PhD programs in April-June 2020. Chi-square and Fisher's exact tests were used to compare differences between groups. Machine learning was employed to select variables for multivariate logistic regression analyses aimed at identifying factors associated with stress and impaired productivity. RESULTS: The analyses included 1,929 respondents (MS: n = 679, 35%; GS: n = 676, 35%; R/F: n = 274, 14%; F: n = 300, 16%). All cohorts reported high levels of social isolation, stress from effects of the pandemic, and negative impacts on productivity. R/F and F respondents were more likely than MS and GS respondents to report financial difficulties due to COVID-19. R/F and F respondents with a dual degree expressed more impaired productivity compared with those without a dual degree. Multivariate regression analyses identified impacted research/scholarly activities, financial difficulties, and social isolation as predictors of stress and impaired productivity for both MS and GS cohorts. For both R/F and F cohorts, impacted personal life and research productivity were associated with stress, while dual-degree status, impacted research/scholarly activities, and impacted personal life were predictors of impaired productivity. More female than male respondents reported increased demands at home. CONCLUSIONS: This national survey of physician-scientist trainees and faculty found a high incidence of stress and impaired productivity related to the COVID-19 pandemic. Understanding the challenges faced and their consequences may improve efforts to support the physician-scientist workforce in the postpandemic period.
Assuntos
Pesquisa Biomédica , COVID-19 , Médicos , Estudantes de Medicina , Pesquisa Biomédica/educação , COVID-19/epidemiologia , Docentes , Feminino , Humanos , Masculino , Pandemias , Estados Unidos/epidemiologiaRESUMO
Phosphatidylinositol-4,5-bisphosphate (PI-4,5-P2 ) is critical for synaptic vesicle docking and fusion and generation of the second messengers, diacylglycerol and inositol-1,4,5-trisphosphate. PI-4,5-P2 can be generated by two families of kinases: type 1 phosphatidylinositol-4-phosphate 5-kinases, encoded by PIP5K1A, PIP5K1B and PIP5K1C, and type 2 phosphatidylinositol-5-phosphate 4-kinases, encoded by PIP4K2A, PIP4K2B, and PIP4K2C. While the roles of the type 1 enzymes in brain function have been extensively studied, the roles of the type 2 enzymes are poorly understood. Using selective antibodies validated by genetic deletion of pip4k2a or pip4k2b in mouse brain, we characterized the location of the enzymes, PI5P4Kα and PI5P4Kß, encoded by these genes. In mice, we demonstrate that PI5P4Kα is expressed in adulthood, whereas PI5P4Kß is expressed early in development. PI5P4Kα localizes to white matter tracts, especially the corpus callosum, and at a low level in neurons, while PI5P4Kß is expressed in neuronal populations, especially hippocampus and cortex. Dual labeling studies demonstrate that PI5P4Kα co-localizes with the oligodendrocyte marker, Olig2, whereas PI5P4Kß co-localizes with the neuronal marker, NeuN. Ultrastructural analysis demonstrates that both kinases are contained in axon terminals and dendritic spines adjacent to the synaptic membrane, which support a potential role in synaptic transmission. Immunoperoxidase analysis of macaque and human brain tissue demonstrate a conserved pattern for PI5P4Kα and PI5P4Kß. These results highlight the diverse cell-autonomous expression of PI5P4Kα and PI5P4Kß and support further exploration into their role in synaptic function in the brain.
Assuntos
Química Encefálica/fisiologia , Encéfalo/embriologia , Encéfalo/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/biossíntese , Animais , Encéfalo/crescimento & desenvolvimento , Feminino , Humanos , Macaca , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfatos de Fosfatidilinositol/análise , Fosfatos de Fosfatidilinositol/biossíntese , Fosfotransferases (Aceptor do Grupo Álcool)/análiseRESUMO
BACKGROUND: Extraneural metastasis of glioma is a rare event, often occurring in patients with advanced disease. Genomic alterations associated with extraneural glioma metastasis remain incompletely understood. METHODS: Ten patients at Memorial Sloan Kettering Cancer Center diagnosed with extraneural metastases of glioblastoma (9 patients) and gliosarcoma (1 patient) from 2003 to 2018 were included in our analysis. Patient characteristics, clinical course, and genomic alterations were evaluated. RESULTS: Patient age at diagnosis ranged from 14 to 73, with 7 men and 3 women in this group. The median overall survival from initial diagnosis and from diagnosis of extraneural metastasis was 19.6 months (range 11.2 to 57.5 months) and 5 months (range 1 to 16.1 months), respectively. The most common site of extraneural metastasis was bone, with other sites being lymph nodes, dura, liver, lung, and soft tissues. All patients received surgical resection and radiation, and 9 patients received temozolomide, with subsequent chemotherapy appropriate for individual cases. 1 patient had an Ommaya and then ventriculoperitoneal shunt placed, and 1 patient underwent craniectomy for cerebral edema associated with a brain abscess at the initial site of resection. Genomic analysis of primary tumors and metastatic sites revealed shared and private mutations with a preponderance of tumor suppressor gene alterations, illustrating clonal evolution in extraneural metastases. CONCLUSIONS: Several risk factors emerged for extraneural metastasis of glioblastoma and gliosarcoma, including sarcomatous dedifferentiation, disruption of normal anatomic barriers during surgical resection, and tumor suppressor gene alterations. Next steps with this work include validation of these genomic markers of glioblastoma metastases in larger patient populations and the development of preclinical models. This work will lead to a better understanding of the molecular mechanisms of metastasis to develop targeted treatments for these patients.
RESUMO
Glioblastoma is one of the most lethal human cancers, with poor survival despite surgery, radiation treatment, and chemotherapy. Advances in the treatment of this type of brain tumor are limited because of several resistance mechanisms. Such mechanisms involve limited drug entry into the central nervous system compartment by the blood-brain barrier and by actions of the normal brain to counteract tumor-targeting medications. In addition, the vast heterogeneity in glioblastoma contributes to significant therapeutic resistance by preventing adequate control of the entire tumor mass by a single drug and by facilitating escape mechanisms from targeted agents. The stem cell-like characteristics of glioblastoma promote resistance to chemotherapy, radiation, and immunotherapy through upregulation of efflux transporters, promotion of glioblastoma stem cell proliferation in neurogenic zones, and immune suppression, respectively. Metabolic cascades in glioblastoma prevent effective treatments through the optimization of glucose use, the use of alternative nutrient precursors for energy production, and the induction of hypoxia to enhance tumor growth. In the era of precision medicine, an assortment of molecular techniques is being developed to target an individual's unique tumor, with the hope that this personalized strategy will bypass therapeutic resistance. Although each resistance mechanism presents an array of challenges to effective treatment of glioblastoma, as the field recognizes and addresses these difficulties, future treatments may have more efficacy and promise for patients with glioblastoma.
Assuntos
Neoplasias Encefálicas/terapia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glioblastoma/terapia , Medicina de Precisão , Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Humanos , Imunoterapia/métodos , Resultado do TratamentoRESUMO
Astrocyte-elevated gene-1 (AEG-1/MTDH/LYRIC) is a potent oncogene that regulates key cellular processes underlying disease of the central nervous system (CNS). From its involvement in human immunodeficiency virus (HIV)-1 infection to its role in neurodegenerative disease and malignant brain tumors, AEG-1/MTDH/LYRIC facilitates cellular survival and proliferation through the control of a multitude of molecular signaling cascades. AEG-1/MTDH/LYRIC induction by HIV-1 and TNF highlights its importance in viral infection, and its incorporation into viral vesicles supports its potential role in active viral replication. Overexpression of AEG-1/MTDH/LYRIC in the brains of Huntington's disease patients suggests its function in neurodegenerative disease, and its association with genetic polymorphisms in large genome-wide association studies of migraine patients suggests a possible role in the pathogenesis of migraine headaches. In the field of cancer, AEG-1/MTDH/LYRIC promotes angiogenesis, migration, invasion, and enhanced tumor metabolism through key oncogenic signaling cascades. In response to external stress cues and cellular mechanisms to inhibit further growth, AEG-1/MTDH/LYRIC activates pathways that bypass cell checkpoints and potentiates signals to enhance survival and tumorigenesis. As an oncogene that promotes aberrant cellular processes within the CNS, AEG-1/MTDH/LYRIC represents an important therapeutic target for the treatment of neurological disease.
Assuntos
Moléculas de Adesão Celular/fisiologia , Doenças do Sistema Nervoso Central/etiologia , Animais , Autofagia/fisiologia , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Sistema Nervoso Central/metabolismo , Doenças do Sistema Nervoso Central/diagnóstico , Doenças do Sistema Nervoso Central/terapia , Resistencia a Medicamentos Antineoplásicos/genética , Estudos de Associação Genética , Humanos , Proteínas de Membrana , Invasividade Neoplásica , Proteínas de Ligação a RNARESUMO
Oncogenic viruses represent a significant public health burden in light of the multitude of malignancies that result from chronic or spontaneous viral infection and transformation. Although many of the molecular signaling pathways that underlie virus-mediated cellular transformation are known, the impact of these viruses on metabolic signaling and phenotype within proliferating tumor cells is less well understood. Whether the interaction of oncogenic viruses with metabolic signaling pathways involves enhanced glucose uptake and glycolysis (both hallmark features of transformed cells) or dysregulation of molecular pathways that regulate oxidative stress, viruses are adept at facilitating tumor expansion. Through their effects on cell proliferation pathways, such as the PI3K and MAPK pathways, the cell cycle regulatory proteins p53 and ATM, and the cell stress response proteins HIF-1α and AMPK, viruses exert control over critical metabolic signaling cascades. Additionally, oncogenic viruses modulate the tumor metabolomic profile through direct and indirect interactions with glucose transporters, such as GLUT1, and specific glycolytic enzymes, including pyruvate kinase, glucose 6-phosphate dehydrogenase, and hexokinase. Through these pathways, oncogenic viruses alter the phenotypic characteristics and energy-use methods of transformed cells; therefore, it may be possible to develop novel antiglycolytic therapies to target these dysregulated pathways in virus-derived malignancies.
Assuntos
Glucose/metabolismo , Redes e Vias Metabólicas , Neoplasias/virologia , Vírus Oncogênicos/metabolismo , Ciclo Celular , Proliferação de Células , Glicólise , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Transdução de Sinais , Estresse FisiológicoRESUMO
Recent studies have reported the detection of the human neurotropic virus, JCV, in a significant population of brain tumors, including medulloblastomas. Accordingly, expression of the JCV early protein, T-antigen, which has transforming activity in cell culture and in transgenic mice, results in the development of a broad range of tumors of neural crest and glial origin. Evidently, the association of T-antigen with a range of tumor-suppressor proteins, including p53 and pRb, and signaling molecules, such as ß-catenin and IRS-1, plays a role in the oncogenic function of JCV T-antigen. We demonstrate that T-antigen expression is suppressed by glucose deprivation in medulloblastoma cells and in glioblastoma xenografts that both endogenously express T-antigen. Mechanistic studies indicate that glucose deprivation-mediated suppression of T-antigen is partly influenced by 5'-activated AMP kinase (AMPK), an important sensor of the AMP/ATP ratio in cells. In addition, glucose deprivation-induced cell cycle arrest in the G1 phase is blocked with AMPK inhibition, which also prevents T-antigen downregulation. Furthermore, T-antigen prevents G1 arrest and sustains cells in the G2 phase during glucose deprivation. On a functional level, T-antigen downregulation is partially dependent on reactive oxygen species (ROS) production during glucose deprivation, and T-antigen prevents ROS induction, loss of ATP production, and cytotoxicity induced by glucose deprivation. Additionally, we have found that T-antigen is downregulated by the glycolytic inhibitor, 2-deoxy-D-glucose (2-DG), and the pentose phosphate inhibitors, 6-aminonicotinamide and oxythiamine, and that T-antigen modulates expression of the glycolytic enzyme, hexokinase 2 (HK2), and the pentose phosphate enzyme, transaldolase-1 (TALDO1), indicating a potential link between T-antigen and metabolic regulation. These studies point to the possible involvement of JCV T-antigen in medulloblastoma proliferation and the metabolic phenotype and may enhance our understanding of the role of viral proteins in glycolytic tumor metabolism, thus providing useful targets for the treatment of virus-induced tumors.
Assuntos
Antígenos Virais de Tumores/metabolismo , Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Glucose/metabolismo , Vírus JC/metabolismo , Meduloblastoma/metabolismo , 6-Aminonicotinamida/farmacologia , Animais , Antígenos Virais de Tumores/análise , Antimetabólitos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/virologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Cricetinae , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Desoxiglucose/farmacologia , Regulação para Baixo , Glioblastoma/tratamento farmacológico , Glioblastoma/virologia , Glicólise/efeitos dos fármacos , Hexoquinase/biossíntese , Humanos , Vírus JC/efeitos dos fármacos , Meduloblastoma/tratamento farmacológico , Meduloblastoma/virologia , Redes e Vias Metabólicas/efeitos dos fármacos , Camundongos , Oxitiamina/farmacologia , Via de Pentose Fosfato/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transaldolase/biossínteseRESUMO
Glioblastomas continue to carry poor prognoses for patients despite advances in surgical, chemotherapeutic, and radiation regimens. One feature of glioblastoma associated with poor prognosis is the degree of hypoxia and expression levels of hypoxia-inducible factor-1 α (HIF-1α). HIF-1α expression allows metabolic adaptation to low oxygen availability, partly through upregulation of VEGF and increased tumor angiogenesis. Here, we demonstrate an induced level of astrocyte-elevated gene-1 (AEG-1) by hypoxia in glioblastoma cells. AEG-1 has the capacity to promote anchorage-independent growth and cooperates with Ha-ras in malignant transformation. In addition, AEG-1 was recently demonstrated to serve as an oncogene and can induce angiogenesis in glioblastoma. Results from in vitro studies show that hypoxic induction of AEG-1 is dependent on HIF-1α stabilization during hypoxia and that PI3K inhibition abrogates AEG-1 induction during hypoxia through loss of HIF-1α stability. Furthermore, we show that AEG-1 is induced by glucose deprivation and that prevention of intracellular reactive oxygen species (ROS) production prevents this induction. Additionally, AEG-1 knockdown results in increased ROS production and increased glucose deprivation-induced cytotoxicity. On the other hand, AEG-1 overexpression prevents ROS production and decreases glucose deprivation-induced cytotoxicity, indicating that AEG-1 induction is necessary for cells to survive this type of cell stress. These observations link AEG-1 overexpression in glioblastoma with hypoxia and glucose deprivation, and targeting these physiological pathways may lead to therapeutic advances in the treatment of glioblastoma in the future.
Assuntos
Moléculas de Adesão Celular/biossíntese , Glioblastoma/metabolismo , Glucose/deficiência , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Hipóxia Celular/fisiologia , Linhagem Celular Tumoral , Glioblastoma/genética , Glucose/metabolismo , Células HEK293 , Humanos , Fator 1 Induzível por Hipóxia/biossíntese , Fator 1 Induzível por Hipóxia/genética , Fator 1 Induzível por Hipóxia/metabolismo , Proteínas de Membrana , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Proteínas de Ligação a RNA , TransfecçãoRESUMO
Glioblastomas continue to rank among the most lethal primary human tumors. Despite treatment with the most rigorous surgical interventions along with the most optimal chemotherapeutic and radiation regimens, the median survival is just 12-15 mo for patients with glioblastoma. Among the histological hallmarks of glioblastoma, necrosis has been demonstrated to be a powerful predictor of poor patient prognosis. Over the years, there have been many advances in our understanding of the molecular mechanisms underlying glioblastoma formation, yet the mechanisms that lead to tumor necrosis remain unclear. One pathway that may lead to necrosis in glioblastoma involves the neurotransmitter, glutamate, which has been shown to accumulate in the peritumoral fluid as a result of decreased cellular uptake by glioblastoma cells. This accumulation leads to subsequent glutamate excitotoxicity and probable necrosis through a massive elevation of intracellular Ca(2+) and reduction in cellular ATP levels. We propose that a pathway involving tumor necrosis factor-alpha (TNFalpha), astrocyte-elevated gene-1 (AEG-1) and nuclear factor-kappaB (NFkappaB) leads to decreased glutamate uptake through coordinated downregulation of the excitatory amino acid transporter 2 (EAAT2), the glutamate transporter responsible for the majority of glutamate uptake in the human brain. In addition, we suggest that AEG-1 signaling, loss of phosphatase and tensin homolog (PTEN), and ionotropic glutamate receptor activity lead to AKT pathway activation, which results in nutrient overconsumption and necrosis. Together, these pathways provide a new perspective on glioblastoma necrosis involving the process of glutamate excitotoxicity. Future research should address the components of these molecular pathways in order to better understand the mechanism of necrosis in glioblastoma and to begin to develop targeted therapies that may improve patient prognosis in the future.