| Autor: |
Ji Min Park, Yen-Hao Su, Chi-Shuan Fan, Hsin-Hua Chen, Yuan-Kai Qiu, Li-Li Chen, Hsin-An Chen, Thamil Selvee Ramasamy, Jung-Su Chang, Shih-Yi Huang, Wun-Shaing Wayne Chang, Alan Yueh-Luen Lee, Tze-Sing Huang, Cheng-Chin Kuo, Ching-Feng Chiu |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
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| Zdroj: |
Experimental and Molecular Medicine, Vol 56, Iss 9, Pp 2065-2081 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2092-6413 |
| DOI: |
10.1038/s12276-024-01300-4 |
| Popis: |
Abstract Ferritin, comprising heavy (FTH1) and light (FTL) chains, is the main iron storage protein, and pancreatic cancer patients exhibit elevated serum ferritin levels. Specifically, higher ferritin levels are correlated with poorer pancreatic ductal adenocarcinoma (PDAC) prognosis; however, the underlying mechanism and metabolic programming of ferritin involved in KRAS-mutant PDAC progression remain unclear. Here, we observed a direct correlation between FTH1 expression and cell viability and clonogenicity in KRAS-mutant PDAC cell lines as well as with in vivo tumor growth through the control of proline metabolism. Our investigation highlights the intricate relationship between FTH1 and pyrroline-5-carboxylate reductase 1 (PYCR1), a crucial mitochondrial enzyme facilitating the glutamate-to-proline conversion, underscoring its impact on proline metabolic imbalance in KRAS-mutant PDAC. This regulation is further reversed by miR-5000-3p, whose dysregulation results in the disruption of proline metabolism, thereby accentuating the progression of KRAS-mutant PDAC. Additionally, our study demonstrated that deferasirox, an oral iron chelator, significantly diminishes cell viability and tumor growth in KRAS-mutant PDAC by targeting FTH1-mediated pathways and altering the PYCR1/PRODH expression ratio. These findings underscore the novel role of FTH1 in proline metabolism and its potential as a target for PDAC therapy development. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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