Periodical
γ-Glutamylcyclotransferase, a novel regulator of HIF-1α expression, triggers aerobic glycolysis
| العنوان: | γ-Glutamylcyclotransferase, a novel regulator of HIF-1α expression, triggers aerobic glycolysis |
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| المؤلفون: | Taniguchi, Keiko, Kageyama, Susumu, Moyama, Chiami, Ando, Shota, Ii, Hiromi, Ashihara, Eishi, Horinaka, Mano, Sakai, Toshiyuki, Kubota, Shigehisa, Kawauchi, Akihiro, Nakata, Susumu |
| المصدر: | Cancer Gene Therapy; 20240101, Issue: Preprints p1-12, 12p |
| مستخلص: | 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. |
| قاعدة البيانات: | Supplemental Index |
| تدمد: | 09291903 14765500 |
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| DOI: | 10.1038/s41417-020-00287-0 |