| RRC ID |
71642
|
| 著者 |
Taniguchi K, Kageyama S, Moyama C, Ando S, Ii H, Ashihara E, Horinaka M, Sakai T, Kubota S, Kawauchi A, Nakata S.
|
| タイトル |
γ-Glutamylcyclotransferase, a novel regulator of HIF-1α expression, triggers aerobic glycolysis.
|
| ジャーナル |
Cancer Gene Ther
|
| Abstract |
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.
|
| 巻・号 |
29(1)
|
| ページ |
37-48
|
| 公開日 |
2022-1-1
|
| DOI |
10.1038/s41417-020-00287-0
|
| PII |
10.1038/s41417-020-00287-0
|
| PMID |
33402732
|
| MeSH |
Animals
Cell Line, Tumor
Citric Acid Cycle*
Glycolysis / genetics
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / genetics
Mice
NIH 3T3 Cells
gamma-Glutamylcyclotransferase* / genetics
|
| IF |
4.534
|
| リソース情報 |
| ヒト・動物細胞 |
A549 |
