Role of AHR and HIF-1α in Glioblastoma Metabolism

Gabriely, Galina; Wheeler, Michael A.; Takenaka, Maisa C.; Quintana, Francisco J.

doi:10.1016/j.tem.2017.02.009

Cited by 98 publications

(68 citation statements)

References 95 publications

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“…Our present study proved that Gen could protect H9c2 cells from CoCl 2 -induced hypoxic injury. Hypoxia is a well-characterized trigger of HIF-1α-dependent signaling [33]. The activation of HIF-1α has been revealed in human hearts under conditions of myocardial hypoxia and infarction [34].…”

Section: Discussionmentioning

confidence: 99%

Genistein Protects H9c2 Cardiomyocytes against Chemical Hypoxia-Induced Injury via Inhibition of Apoptosis

Shi¹,

Zhang²,

Hu³

et al. 2019

Pharmacology

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Background/Aims: Hypoxia can induce cell injury in cardiomyocytes and further lead to cardiovascular diseases. Genistein (Gen), the predominant isoflavone found in soy products, has shown protective effects on cardiovascular system. The aim of the present study was to investigate the cardioprotective effect of Gen against chemical hypoxia-induced injury. Methods: Cobalt chloride (CoCl₂) was administrated to trigger chemical hypoxia in H9c2 cardiomyocytes. Cell proliferation was detected by using MTT assay. The expression level of hypoxia-related proteins (hypoxia-inducible factor [HIF]-1α and Notch-1) and apoptosis-related proteins (B cell lymphoma [Bcl]-2, Bax, and caspase-3) were evaluated by Western blot analysis. Results: In response to hypoxia, cell viability was reduced dramatically, whereas the expression of HIF-1α was upregulated. Hypoxia also induced cardiomyocytes apoptosis by reducing the ratio of Bcl-2/Bax and increasing expression of caspase-3. Interestingly, Gen attenuated CoCl₂-induced cell death and suppressed HIF-1α expression, as well as upregulated the expression of Notch-1. Furthermore, Gen could antagonize CoCl₂-induced apoptosis through upregulating Bcl-2/Bax ratio and inhibiting caspase-3 expression. Conclusions: Gen prevents chemical hypoxia-induced cell apoptosis through inhibition of the mitochondrial apoptotic pathway, exerting protective effects on H9c2 cardiomyocytes.

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Section: Discussionmentioning

confidence: 99%

Genistein Protects H9c2 Cardiomyocytes against Chemical Hypoxia-Induced Injury via Inhibition of Apoptosis

Shi¹,

Zhang²,

Hu³

et al. 2019

Pharmacology

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“…Cariporide treatment has been shown to reduce NHE1 mRNA and protein expression in isolated rat renal cortex 46 . Glioma hypoxic microenvironment and acidosis stimulate the HIF-1α expression 47 , 48 , which may result in upregulation of NHE1 expression and promote the acidic microenvironment 49 – 51 . Therefore, inhibition of NHE1 activity with HOE642 could relieve the acidic, hypoxic microenvironment and reduce HIF-1α expression, leading to the downregulation of NHE1 protein expression.…”

Section: Discussionmentioning

confidence: 99%

Blockade of Na/H exchanger stimulates glioma tumor immunogenicity and enhances combinatorial TMZ and anti-PD-1 therapy

et al. 2018

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The weak immunogenicity of gliomas presents a barrier for effective immunotherapy. Na/H exchanger isoform 1 (NHE1) maintains alkaline intracellular pH (pHi) of glioma cells and acidic microenvironment. In addition, NHE1 is expressed in tumor-associated microglia and tumor-associated macrophages (TAMs) and involved in protumoral communications between glioma and TAMs. Therefore, we hypothesize that NHE1 plays a role in developing tumor resistance and immunosuppressive tumor microenvironment. In this study, we investigated the efficacy of pharmacological inhibition of NHE1 on combinatorial therapies. Here we show that temozolomide (TMZ) treatment stimulates NHE1 protein expression in two intracranial syngeneic mouse glioma models (SB28, GL26). Pharmacological inhibition of NHE1 potentiated the cytotoxic effects of TMZ, leading to reduced tumor growth and increased median survival of mice. Blockade of NHE1 stimulated proinflammatory activation of TAM and increased cytotoxic T cell infiltration into tumors. Combining TMZ, anti-PD-1 antibody treatment with NHE1 blockade significantly prolonged the median survival in the mouse glioma model. These results demonstrate that pharmacological inhibition of NHE1 protein presents a new strategy for potentiating TMZ-induced cytotoxicity and increasing tumor immunogenicity for immunotherapy to improve glioma therapy.

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“…Here, we performed bioinformatic analysis on RLIP76 coexpressed genes from the TCGA GBM database and found that RLIP76 plays a crucial role in the reduction of oxidative phosphorylation and ubiquitinmediated proteolysis in GBM. It has been well documented that the ubiquitin-and proteasome-mediated degradation of HIF-1α plays a pivotal role in enhanced glycolysis in GBM [37]. Under hypoxic conditions, HIF-1α can escape ubiquitin-mediated proteolysis by disassociating with VHL, a component of an E3 ubiquitin-protein ligase complex [38].…”

Section: Discussionmentioning

confidence: 99%

The Positive Feedback Loop Between RLIP76 and HIF-1α Promotes Glycolysis and Tumorigenesis in Glioma Cells Under Hypoxic Conditions

Wang¹,

Zhang²,

Zhang³

et al. 2020

Preprint

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BackgroundHypoxia is intimately associated with increased glycolysis in gliomas, and HIF-1α plays a critical role in this process. Here, we aim to show that RLIP76 is a novel target of HIF-1α and is involved in hypoxia-enhanced glycolysis in glioma cells. MethodsThe human glioma cell lines U87 and U251 were used to explore the interactions of RLIP76-HIF-1α and RLIP76-VHL using Western blot, a Biotin pull-down assay, Immunoprecipitation, and a Chromatin immunoprecipitation assay under hypoxia. U251 cells pretreated with hypoxia were used for tumor xenografts. ResultsRLIP76 is a novel target of HIF-1α and contributes to hypoxia-enhanced glycolysis in glioma cells. HIF-1α-induced RLIP76 can critically regulate the stability of HIF-1α by alleviating VHL-mediated HIF-1α ubiquitination under hypoxia. RLIP76 interacts with HIF-1α and VHL through an RLIP76 GAP-dependent mechanism. The GAP function of RLIP76 regulates its complex formation because of the dependence of RLIP76 GAP on interactions between RLIP76 and these proteins. RLIP76 knockdown results in decreased U251 cell growth after hypoxia pretreatment in vivo. ConclusionsThis study reveals a positive feedback loop between HIF-1α and RLIP76, suggesting that RLIP76 may undergo a complex series of GAP-dependent interactions with HIF-1α and VHL to protect HIF-1α from degradation while promoting glycolysis under hypoxic conditions. We indicate that RLIP76 is crucial for the regulation of hypoxia-enhanced glycolysis and may provide a new gene therapy approach for glioma patients.

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Role of AHR and HIF-1α in Glioblastoma Metabolism

Cited by 98 publications

References 95 publications

Genistein Protects H9c2 Cardiomyocytes against Chemical Hypoxia-Induced Injury via Inhibition of Apoptosis

Genistein Protects H9c2 Cardiomyocytes against Chemical Hypoxia-Induced Injury via Inhibition of Apoptosis

Blockade of Na/H exchanger stimulates glioma tumor immunogenicity and enhances combinatorial TMZ and anti-PD-1 therapy

The Positive Feedback Loop Between RLIP76 and HIF-1α Promotes Glycolysis and Tumorigenesis in Glioma Cells Under Hypoxic Conditions

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