{"title":"<i>PYGL</i> regulation of glycolysis and apoptosis in glioma cells under hypoxic conditions via HIF1α-dependent mechanisms.","authors":"Tingyu Cao, Jinchun Wang","doi":"10.21037/tcr-24-1974","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Gliomas are highly aggressive brain tumors with complex metabolic and molecular alterations. The role of glycolysis in glioma progression and its regulation by hypoxia remain poorly understood. This study investigated the function of glycogen phosphorylase L (<i>PYGL</i>) in glioma and its interaction with glycolytic pathways under hypoxic conditions.</p><p><strong>Methods: </strong>Differential expression analysis was conducted using The Cancer Genome Atlas (TCGA) glioma and GSE67089 datasets, revealing significant changes in the expression of genes. A prognostic risk model incorporating <i>PYGL</i> was built by univariate and multivariate Cox regression analyses. The impacts of <i>PYGL</i> on glioma cell proliferation, glycolysis, apoptosis, and metabolic activities were evaluated by <i>in vitro</i> assays. Additionally, the influences of hypoxia and hypoxia-inducible factor 1-alpha (<i>HIF1α</i>) on <i>PYGL</i> expression were evaluated.</p><p><strong>Results: </strong>Our prognostic prediction model showed a C-index of 0.76 [95% confidence interval (CI): 0.70-0.82], indicating a good predictive accuracy of the model. In addition, genetic predictors included in the nomogram included PYGL, HIF1α, and other genes associated with the glycolytic pathway. Differential expression analysis identified <i>PYGL</i> as a key gene associated with glioma survival. <i>PYGL</i> expression was significantly upregulated in glioma cells. <i>PYGL</i> knockdown inhibited cell invasion, proliferation, migration, and colony formation and enhanced apoptosis via modulation of Bcl-2, caspase-3, and Bax. Glycolysis was impaired in <i>PYGL</i>-knockdown cells, as indicated by increased glycogen levels and a reduced extracellular acidification rate (ECAR), adenosine triphosphate (ATP) levels, lactate levels, and PKM2 and LDHA expression. <i>PYGL</i> overexpression promoted glycolysis and cell viability, which was counteracted by 2-deoxy-D-glucose (2-DG). Hypoxia-induced <i>PYGL</i> expression was regulated by <i>HIF1α</i>, underscoring the interplay between the hypoxia and glycolysis pathways.</p><p><strong>Conclusions: </strong><i>PYGL</i> is a crucial regulator of glycolysis in gliomas and contributes to tumor progression under hypoxic conditions. Targeting <i>PYGL</i> and its associated metabolic pathways may offer new therapeutic strategies for glioma treatment.</p>","PeriodicalId":23216,"journal":{"name":"Translational cancer research","volume":"13 10","pages":"5627-5648"},"PeriodicalIF":1.5000,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11543057/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Translational cancer research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.21037/tcr-24-1974","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/10/29 0:00:00","PubModel":"Epub","JCR":"Q4","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Gliomas are highly aggressive brain tumors with complex metabolic and molecular alterations. The role of glycolysis in glioma progression and its regulation by hypoxia remain poorly understood. This study investigated the function of glycogen phosphorylase L (PYGL) in glioma and its interaction with glycolytic pathways under hypoxic conditions.
Methods: Differential expression analysis was conducted using The Cancer Genome Atlas (TCGA) glioma and GSE67089 datasets, revealing significant changes in the expression of genes. A prognostic risk model incorporating PYGL was built by univariate and multivariate Cox regression analyses. The impacts of PYGL on glioma cell proliferation, glycolysis, apoptosis, and metabolic activities were evaluated by in vitro assays. Additionally, the influences of hypoxia and hypoxia-inducible factor 1-alpha (HIF1α) on PYGL expression were evaluated.
Results: Our prognostic prediction model showed a C-index of 0.76 [95% confidence interval (CI): 0.70-0.82], indicating a good predictive accuracy of the model. In addition, genetic predictors included in the nomogram included PYGL, HIF1α, and other genes associated with the glycolytic pathway. Differential expression analysis identified PYGL as a key gene associated with glioma survival. PYGL expression was significantly upregulated in glioma cells. PYGL knockdown inhibited cell invasion, proliferation, migration, and colony formation and enhanced apoptosis via modulation of Bcl-2, caspase-3, and Bax. Glycolysis was impaired in PYGL-knockdown cells, as indicated by increased glycogen levels and a reduced extracellular acidification rate (ECAR), adenosine triphosphate (ATP) levels, lactate levels, and PKM2 and LDHA expression. PYGL overexpression promoted glycolysis and cell viability, which was counteracted by 2-deoxy-D-glucose (2-DG). Hypoxia-induced PYGL expression was regulated by HIF1α, underscoring the interplay between the hypoxia and glycolysis pathways.
Conclusions: PYGL is a crucial regulator of glycolysis in gliomas and contributes to tumor progression under hypoxic conditions. Targeting PYGL and its associated metabolic pathways may offer new therapeutic strategies for glioma treatment.
期刊介绍：
Translational Cancer Research (Transl Cancer Res TCR; Print ISSN: 2218-676X; Online ISSN 2219-6803; http://tcr.amegroups.com/) is an Open Access, peer-reviewed journal, indexed in Science Citation Index Expanded (SCIE). TCR publishes laboratory studies of novel therapeutic interventions as well as clinical trials which evaluate new treatment paradigms for cancer; results of novel research investigations which bridge the laboratory and clinical settings including risk assessment, cellular and molecular characterization, prevention, detection, diagnosis and treatment of human cancers with the overall goal of improving the clinical care of cancer patients. The focus of TCR is original, peer-reviewed, science-based research that successfully advances clinical medicine toward the goal of improving patients'' quality of life. The editors and an international advisory group of scientists and clinician-scientists as well as other experts will hold TCR articles to the high-quality standards. We accept Original Articles as well as Review Articles, Editorials and Brief Articles.
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