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

IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Experimental and Molecular Medicine Pub Date : 2024-09-18 DOI:10.1038/s12276-024-01300-4
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
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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.

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FTH1 和 PYCR1 之间的相互影响会导致脯氨酸代谢失调,并介导 KRAS 突变胰腺癌细胞的生长
铁蛋白由重链(FTH1)和轻链(FTL)组成,是主要的铁储存蛋白,胰腺癌患者的血清铁蛋白水平会升高。具体而言,较高的铁蛋白水平与较差的胰腺导管腺癌(PDAC)预后相关;然而,铁蛋白参与 KRAS 突变型 PDAC 进展的潜在机制和代谢程序仍不清楚。在这里,我们观察到 FTH1 的表达与 KRAS 突变 PDAC 细胞系的细胞活力和克隆性直接相关,并且通过控制脯氨酸代谢与体内肿瘤生长直接相关。我们的研究强调了FTH1与吡咯啉-5-羧酸还原酶1(PYCR1)之间错综复杂的关系,PYCR1是促进谷氨酸-脯氨酸转化的线粒体关键酶,强调了它对KRAS突变型PDAC中脯氨酸代谢失衡的影响。miR-5000-3p 进一步逆转了这种调控,其失调导致脯氨酸代谢紊乱,从而加剧了 KRAS 突变型 PDAC 的进展。此外,我们的研究表明,口服铁螯合剂地拉羅司通过靶向 FTH1 介导的通路和改变PYCR1/PRODH 的表达比,显著降低了 KRAS 突变型 PDAC 的细胞活力和肿瘤生长。这些发现强调了 FTH1 在脯氨酸代谢中的新作用及其作为 PDAC 治疗开发靶点的潜力。
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来源期刊
Experimental and Molecular Medicine
Experimental and Molecular Medicine 医学-生化与分子生物学
CiteScore
19.50
自引率
0.80%
发文量
166
审稿时长
3 months
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.
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