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γ-谷氨酰环转移酶是一种新的HIF-1α表达调节因子，可触发有氧糖酵解

γ-Glutamylcyclotransferase, a novel regulator of HIF-1α expression, triggers aerobic glycolysis

原文发布日期：2021-01-05

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γ-谷氨酰环转移酶是一种新的HIF-1α表达调节因子，可触发有氧糖酵解

γ-Glutamylcyclotransferase, a novel regulator of HIF-1α expression, triggers aerobic glycolysis

原文发布日期：2021-01-05

英文摘要：

Metabolic reprogramming leading to aerobic glycolysis, termed the “Warburg effect,” is a critical property of cancer cells. However, the precise mechanisms underlying this phenomenon are not fully understood. A growing body of evidence indicates that γ-glutamylcyclotransferase (GGCT), an enzyme involved in glutathione homeostasis that is highly expressed in many types of cancer, represents a promising therapeutic target. In this study, we identified GGCT as a novel regulator of hypoxia-inducible factor-1α (HIF-1α), a transcription factor that plays a role in hypoxia adaptation promoting aerobic glycolysis. In multiple human cancer cell lines, depletion of GGCT downregulated HIF-1α at the mRNA and protein levels. Conversely, in NIH3T3 mouse fibroblasts, overexpression of GGCT upregulated HIF-1α under normoxia. Moreover, depletion of GGCT downregulated HIF-1α downstream target genes involved in glycolysis, whereas overexpression of GGCT upregulated those genes. Metabolomic analysis revealed that modulation of GGCT expression induced a metabolic switch from the citric acid cycle to glycolysis under normoxia. In addition, we found that GGCT regulates expression of HIF-1α protein via the AMPK–mTORC1–4E-BP1 pathway in PC3 cells. Thus GGCT regulates the expression of HIF-1α in cancer cells, causing a switch to glycolysis.

摘要翻译：

导致有氧糖酵解的代谢重编程（称为“瓦博格效应”）是癌细胞的关键特性。然而，这一现象的确切机制尚未完全阐明。越来越多的证据表明，γ-谷氨酰环转移酶（GGCT）——一种参与谷胱甘肽稳态且在多种癌症中高表达的酶，是一个潜在的治疗靶点。本研究首次发现GGCT是缺氧诱导因子-1α（HIF-1α）的新型调控因子，这种转录因子在促进有氧糖酵解的缺氧适应过程中发挥重要作用。在多种人类癌细胞系中，敲低GGCT可在mRNA和蛋白水平下调HIF-1α表达；相反，在NIH3T3小鼠成纤维细胞中，常氧条件下过表达GGCT可上调HIF-1α。进一步研究发现，敲低GGCT可下调糖酵解相关HIF-1α下游靶基因，而过表达GGCT则能上调这些基因。代谢组学分析表明，在常氧条件下调节GGCT表达可诱导代谢从三羧酸循环向糖酵解转变。此外，我们在PC3细胞中发现GGCT通过AMPK–mTORC1–4E-BP1信号通路调控HIF-1α蛋白表达。这些结果表明，GGCT通过调控癌细胞中HIF-1α的表达驱动糖酵解代谢重编程。