한빛사논문
- 조회397
Ji Min Park 1,2,3, Yen-Hao Su 4,5,6, Chi-Shuan Fan 7, Hsin-Hua Chen 1, Yuan-Kai Qiu 1,2, Li-Li Chen 7, Hsin-An Chen 4,5,6, Thamil Selvee Ramasamy 8, Jung-Su Chang 1,2,9, Shih-Yi Huang 1,2, Wun-Shaing Wayne Chang 7, Alan Yueh-Luen Lee 7, Tze-Sing Huang 7, Cheng-Chin Kuo 3,10,* and Ching-Feng Chiu 1,6,9,11,*
1Graduate Institute of Metabolism and Obesity Sciences, Taipei Medical University, Taipei, Taiwan.
2School of Nutrition and Health Sciences, Taipei Medical University, Taipei, Taiwan.
3Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan.
4Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
5Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
6TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan.
7National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan.
8Stem Cell Biology Laboratory, Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia.
9Nutrition Research Center, Taipei Medical University Hospital, Taipei, Taiwan.
10Department of Bioscience Technology, Chung Yuan Christian University, Taoyuan, Taiwan.
11Taipei Medical University and Affiliated Hospitals Pancreatic Cancer Groups, Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan.
*Corresponding authors: correspondence to Cheng-Chin Kuo or Ching-Feng Chiu
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.
논문정보
- Research article
- 2024년 09월 (BRIC 등록일 2024-09-24)
- 국외 연구진
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