Crosstalk between FTH1 and PYCR1 dysregulates proline metabolism and mediates cell growth in KRAS-mutant pancreatic cancer cells.

Autor: Park JM; Graduate Institute of Metabolism and Obesity Sciences, Taipei Medical University, Taipei, Taiwan.; School of Nutrition and Health Sciences, Taipei Medical University, Taipei, Taiwan.; Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan., Su YH; Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.; Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan., Fan CS; National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan., Chen HH; Graduate Institute of Metabolism and Obesity Sciences, Taipei Medical University, Taipei, Taiwan., Qiu YK; Graduate Institute of Metabolism and Obesity Sciences, Taipei Medical University, Taipei, Taiwan.; School of Nutrition and Health Sciences, Taipei Medical University, Taipei, Taiwan., Chen LL; National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan., Chen HA; Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.; Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan., Ramasamy TS; Stem Cell Biology Laboratory, Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, 50603, Malaysia., Chang JS; Graduate Institute of Metabolism and Obesity Sciences, Taipei Medical University, Taipei, Taiwan.; School of Nutrition and Health Sciences, Taipei Medical University, Taipei, Taiwan.; Nutrition Research Center, Taipei Medical University Hospital, Taipei, Taiwan., Huang SY; Graduate Institute of Metabolism and Obesity Sciences, Taipei Medical University, Taipei, Taiwan.; School of Nutrition and Health Sciences, Taipei Medical University, Taipei, Taiwan., Chang WW; National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan., Lee AY; National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan., Huang TS; National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan., Kuo CC; Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan. kuocc@nhri.org.tw.; Department of Bioscience Technology, Chung Yuan Christian University, Taoyuan, Taiwan. kuocc@nhri.org.tw., Chiu CF; Graduate Institute of Metabolism and Obesity Sciences, Taipei Medical University, Taipei, Taiwan. chiucf@tmu.edu.tw.; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan. chiucf@tmu.edu.tw.; Nutrition Research Center, Taipei Medical University Hospital, Taipei, Taiwan. chiucf@tmu.edu.tw.; Taipei Medical University and Affiliated Hospitals Pancreatic Cancer Groups, Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan. chiucf@tmu.edu.tw.
Jazyk: angličtina
Zdroj: Experimental & molecular medicine [Exp Mol Med] 2024 Sep; Vol. 56 (9), pp. 2065-2081. Date of Electronic Publication: 2024 Sep 18.
DOI: 10.1038/s12276-024-01300-4
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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