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
{"title":"Crosstalk between FTH1 and PYCR1 dysregulates proline metabolism and mediates cell growth in KRAS-mutant pancreatic cancer cells","authors":"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","doi":"10.1038/s12276-024-01300-4","DOIUrl":null,"url":null,"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. Iron storage in our body is mainly controlled by a protein named ferritin, which reflects the amount of stored iron through its blood levels. Low ferritin levels usually suggest iron-deficiency anemia, while high levels can indicate inflammation and hinting at ferritin’s potential as a cancer indicator. In this study, scientists focused on pancreatic cancer, notorious for its low survival rates and limited treatment options. They examined the expression of different ferritin components and their link with the KRAS mutation, a common characteristic in pancreatic cancer that promotes tumor growth. The main discovery is that high FTH1 expression is associated with worse survival in pancreatic cancer patients, suggesting that targeting FTH1 could be a promising treatment for this aggressive cancer. This study enhances our knowledge of the molecular processes driving pancreatic cancer and opens new paths for targeted treatments. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 9","pages":"2065-2081"},"PeriodicalIF":9.5000,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01300-4.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Experimental and Molecular Medicine","FirstCategoryId":"3","ListUrlMain":"https://www.nature.com/articles/s12276-024-01300-4","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
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. Iron storage in our body is mainly controlled by a protein named ferritin, which reflects the amount of stored iron through its blood levels. Low ferritin levels usually suggest iron-deficiency anemia, while high levels can indicate inflammation and hinting at ferritin’s potential as a cancer indicator. In this study, scientists focused on pancreatic cancer, notorious for its low survival rates and limited treatment options. They examined the expression of different ferritin components and their link with the KRAS mutation, a common characteristic in pancreatic cancer that promotes tumor growth. The main discovery is that high FTH1 expression is associated with worse survival in pancreatic cancer patients, suggesting that targeting FTH1 could be a promising treatment for this aggressive cancer. This study enhances our knowledge of the molecular processes driving pancreatic cancer and opens new paths for targeted treatments. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
期刊介绍:
Experimental & Molecular Medicine (EMM) stands as Korea's pioneering biochemistry journal, established in 1964 and rejuvenated in 1996 as an Open Access, fully peer-reviewed international journal. Dedicated to advancing translational research and showcasing recent breakthroughs in the biomedical realm, EMM invites submissions encompassing genetic, molecular, and cellular studies of human physiology and diseases. Emphasizing the correlation between experimental and translational research and enhanced clinical benefits, the journal actively encourages contributions employing specific molecular tools. Welcoming studies that bridge basic discoveries with clinical relevance, alongside articles demonstrating clear in vivo significance and novelty, Experimental & Molecular Medicine proudly serves as an open-access, online-only repository of cutting-edge medical research.