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.

导致有氧糖酵解的代谢重编程，称为“Warburg 效应”，是癌细胞的关键特性。然而，这种现象背后的确切机制尚不完全清楚。越来越多的证据表明，γ-谷氨酰环转移酶 (GGCT) 是一种在多种癌症中高度表达的参与谷胱甘肽稳态的酶，它代表了一个有希望的治疗靶点。在这项研究中，我们将 GGCT 鉴定为缺氧诱导因子-1α (HIF-1α) 的新型调节因子，HIF-1α 是一种在缺氧适应促进有氧糖酵解中起作用的转录因子。在多种人类癌细胞系中，GGCT 的消耗在 mRNA 和蛋白质水平上下调 HIF-1α。相反，在 NIH3T3 小鼠成纤维细胞中，GGCT 的过表达上调了常氧条件下的 HIF-1α。而且，GGCT的消耗下调了参与糖酵解的HIF-1α下游靶基因，而GGCT的过表达上调了这些基因。代谢组学分析显示，调节 GGCT 表达诱导了在常氧条件下从柠檬酸循环到糖酵解的代谢转换。此外，我们发现 GGCT 通过 AMPK-mTORC1-4E-BP1 通路在 PC3 细胞中调节 HIF-1α 蛋白的表达。因此，GGCT 调节癌细胞中 HIF-1α 的表达，导致转变为糖酵解。我们发现GGCT通过AMPK-mTORC1-4E-BP1通路在PC3细胞中调节HIF-1α蛋白的表达。因此，GGCT 调节癌细胞中 HIF-1α 的表达，导致转变为糖酵解。我们发现GGCT通过AMPK-mTORC1-4E-BP1通路在PC3细胞中调节HIF-1α蛋白的表达。因此，GGCT 调节癌细胞中 HIF-1α 的表达，导致转变为糖酵解。