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Ru Q, Li Y, Zhang X, Chen L, Wu Y, Min J, Wang F. Iron homeostasis and ferroptosis in muscle diseases and disorders: mechanisms and therapeutic prospects. Bone Res 2025; 13:27. [PMID: 40000618 PMCID: PMC11861620 DOI: 10.1038/s41413-024-00398-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 11/23/2024] [Accepted: 12/16/2024] [Indexed: 02/27/2025] Open
Abstract
The muscular system plays a critical role in the human body by governing skeletal movement, cardiovascular function, and the activities of digestive organs. Additionally, muscle tissues serve an endocrine function by secreting myogenic cytokines, thereby regulating metabolism throughout the entire body. Maintaining muscle function requires iron homeostasis. Recent studies suggest that disruptions in iron metabolism and ferroptosis, a form of iron-dependent cell death, are essential contributors to the progression of a wide range of muscle diseases and disorders, including sarcopenia, cardiomyopathy, and amyotrophic lateral sclerosis. Thus, a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention. This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury, as well as associated muscle diseases and disorders. Moreover, we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders. Finally, we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.
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Affiliation(s)
- Qin Ru
- Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan, China
| | - Yusheng Li
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Xi Zhang
- Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan, China
| | - Lin Chen
- Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan, China
| | - Yuxiang Wu
- Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan, China.
| | - Junxia Min
- The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
| | - Fudi Wang
- The Second Affiliated Hospital, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, China.
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Xie Z, Hou Q, He Y, Xie Y, Mo Q, Wang Z, Zhao Z, Chen X, Peng T, Li L, Xie W. Ferritin Hinders Ferroptosis in Non-Tumorous Diseases: Regulatory Mechanisms and Potential Consequences. Curr Protein Pept Sci 2025; 26:89-104. [PMID: 39225224 DOI: 10.2174/0113892037315874240826112422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Revised: 07/19/2024] [Accepted: 07/25/2024] [Indexed: 09/04/2024]
Abstract
Ferritin, as an iron storage protein, has the potential to inhibit ferroptosis by reducing excess intracellular free iron concentrations and lipid reactive oxygen species (ROS). An insufficient amount of ferritin is one of the conditions that can lead to ferroptosis through the Fenton reaction mediated by ferrous iron. Consequently, upregulation of ferritin at the transcriptional or posttranscriptional level may inhibit ferroptosis. In this review, we have discussed the essential role of ferritin in ferroptosis and the regulatory mechanism of ferroptosis in ferritin-deficient individuals. The description of the regulatory factors governing ferritin and its properties in regulating ferroptosis as underlying mechanisms for the pathologies of diseases will allow potential therapeutic approaches to be developed.
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Affiliation(s)
- Zhongcheng Xie
- Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China
| | - Qin Hou
- Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China
| | - Yinling He
- Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China
| | - Yushu Xie
- Class of Clinical Medicine, University of South China, Hengyang 421001, Hunan, China
| | - Qinger Mo
- Class of Clinical Medicine, University of South China, Hengyang 421001, Hunan, China
| | - Ziyi Wang
- Class of Clinical Medicine, University of South China, Hengyang 421001, Hunan, China
| | - Ziye Zhao
- Class of Clinical Medicine, University of South China, Hengyang 421001, Hunan, China
| | - Xi Chen
- Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China
| | - Tianhong Peng
- Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China
| | - Liang Li
- Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China
| | - Wei Xie
- Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China
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Peng C, Chen Y, Jiang M. Targeting ferroptosis: a promising strategy to overcome drug resistance in breast cancer. Front Oncol 2024; 14:1499125. [PMID: 39759144 PMCID: PMC11695291 DOI: 10.3389/fonc.2024.1499125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 12/04/2024] [Indexed: 01/07/2025] Open
Abstract
Breast cancer is one of the most prevalent malignancies affecting women worldwide, with its incidence increasingly observed in younger populations. In recent years, drug resistance has emerged as a significant challenge in the treatment of breast cancer, making it a central focus of contemporary research aimed at identifying strategies to overcome this issue. Growing evidence indicates that inducing ferroptosis through various mechanisms, particularly by inhibiting System Xc-, depleting glutathione (GSH), and inactivating glutathione peroxidase 4 (GPX4), holds great potential in overcoming drug resistance in breast cancer. It is anticipated that therapies targeting ferroptosis will emerge as a promising strategy to reverse tumor resistance, offering new hope for breast cancer patients. This review will explore the latest advancements in understanding ferroptosis in the context of breast cancer drug resistance, with a particular emphasis on the roles of ferroptosis inducers and inhibitors, and the impact of ferroptotic pathways on overcoming drug resistance in breast cancer.
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Patel MZ, Jiang Y, Kakumani PK. Somatic piRNA and PIWI-mediated post-transcriptional gene regulation in stem cells and disease. Front Cell Dev Biol 2024; 12:1495035. [PMID: 39717847 PMCID: PMC11663942 DOI: 10.3389/fcell.2024.1495035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 11/25/2024] [Indexed: 12/25/2024] Open
Abstract
PIWI-interacting RNAs (piRNAs) are small non-coding RNAs that bind to the PIWI subclass of the Argonaute protein family and are essential for maintaining germline integrity. Initially discovered in Drosophila, PIWI proteins safeguard piRNAs, forming ribonucleoprotein (RNP) complexes, crucial for regulating gene expression and genome stability, by suppressing transposable elements (TEs). Recent insights revealed that piRNAs and PIWI proteins, known for their roles in germline maintenance, significantly influence mRNA stability, translation and retrotransposon silencing in both stem cells and bodily tissues. In the current review, we explore the multifaceted roles of piRNAs and PIWI proteins in numerous biological contexts, emphasizing their involvement in stem cell maintenance, differentiation, and the development of human diseases. Additionally, we discussed the up-and-coming animal models, beyond the classical fruit fly and earthworm systems, for studying piRNA-PIWIs in self-renewal and cell differentiation. Further, our review offers new insights and discusses the emerging roles of piRNA-dependent and independent functions of PIWI proteins in the soma, especially the mRNA regulation at the post-transcriptional level, governing stem cell characteristics, tumor development, and cardiovascular and neurodegenerative diseases.
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Affiliation(s)
| | | | - Pavan Kumar Kakumani
- Department of Biochemistry, Memorial University of Newfoundland, St. John’s, NL, Canada
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Maimaitiyiming A, An H, Xing C, Li X, Li Z, Bai J, Luo C, Zhuo T, Huang X, Maimaiti A, Aikemu A, Wang Y. Machine learning-driven mast cell gene signatures for prognostic and therapeutic prediction in prostate cancer. Heliyon 2024; 10:e35157. [PMID: 39170129 PMCID: PMC11336432 DOI: 10.1016/j.heliyon.2024.e35157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 07/23/2024] [Accepted: 07/24/2024] [Indexed: 08/23/2024] Open
Abstract
Background The role of Mast cells has not been thoroughly explored in the context of prostate cancer's (PCA) unpredictable prognosis and mixed immunotherapy outcomes. Our research aims to employs a comprehensive computational methodology to evaluate Mast cell marker gene signatures (MCMGS) derived from a global cohort of 1091 PCA patients. This approach is designed to identify a robust biomarker to assist in prognosis and predicting responses to immunotherapy. Methods This study initially identified mast cell-associated biomarkers from prostate adenocarcinoma (PRAD) patients across six international cohorts. We employed a variety of machine learning techniques, including Random Forest, Support Vector Machine (SVM), Lasso regression, and the Cox Proportional Hazards Model, to develop an effective MCMGS from candidate genes. Subsequently, an immunological assessment of MCMGS was conducted to provide new insights into the evaluation of immunotherapy responses and prognostic assessments. Additionally, we utilized Gene Set Enrichment Analysis (GSEA) and pathway analysis to explore the biological pathways and mechanisms associated with MCMGS. Results MCMGS incorporated 13 marker genes and was successful in segregating patients into distinct high- and low-risk categories. Prognostic efficacy was confirmed by survival analysis incorporating MCMGS scores, alongside clinical parameters such as age, T stage, and Gleason scores. High MCMGS scores were correlated with upregulated pathways in fatty acid metabolism and β-alanine metabolism, while low scores correlated with DNA repair mechanisms, homologous recombination, and cell cycle progression. Patients classified as low-risk displayed increased sensitivity to drugs, indicating the utility of MCMGS in forecasting responses to immune checkpoint inhibitors. Conclusion The combination of MCMGS with a robust machine learning methodology demonstrates considerable promise in guiding personalized risk stratification and informing therapeutic decisions for patients with PCA.
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Affiliation(s)
- Abudukeyoumu Maimaitiyiming
- The First Affiliated Hospital, Xinjiang Medical University, Urumqi, China
- Department of Urological, Urology Centre, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Hengqing An
- The First Affiliated Hospital, Xinjiang Medical University, Urumqi, China
- Department of Urological, Urology Centre, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
- Xinjiang Clinical Research Center of Urogenital Diseases, Urumqi, China
| | - Chen Xing
- The First Affiliated Hospital, Xinjiang Medical University, Urumqi, China
- Department of Urological, Urology Centre, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
- Xinjiang Clinical Research Center of Urogenital Diseases, Urumqi, China
| | - Xiaodong Li
- The First Affiliated Hospital, Xinjiang Medical University, Urumqi, China
- Department of Urological, Urology Centre, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
- Xinjiang Clinical Research Center of Urogenital Diseases, Urumqi, China
| | - Zhao Li
- Department of Abdominal Ultrasonography, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Junbo Bai
- Department of Pediatric Urology, Urology Centre, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Cheng Luo
- The First Affiliated Hospital, Xinjiang Medical University, Urumqi, China
- Department of Urological, Urology Centre, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Tao Zhuo
- The First Affiliated Hospital, Xinjiang Medical University, Urumqi, China
- Department of Urological, Urology Centre, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Xin Huang
- The First Affiliated Hospital, Xinjiang Medical University, Urumqi, China
- Department of Urological, Urology Centre, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Aierpati Maimaiti
- The First Affiliated Hospital, Xinjiang Medical University, Urumqi, China
- Department of Neurosurgery, Neurosurgery Centre, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | | | - Yujie Wang
- The First Affiliated Hospital, Xinjiang Medical University, Urumqi, China
- Department of Urological, Urology Centre, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
- Xinjiang Clinical Research Center of Urogenital Diseases, Urumqi, China
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Liu D, Hu Z, Lu J, Yi C. Redox-Regulated Iron Metabolism and Ferroptosis in Ovarian Cancer: Molecular Insights and Therapeutic Opportunities. Antioxidants (Basel) 2024; 13:791. [PMID: 39061859 PMCID: PMC11274267 DOI: 10.3390/antiox13070791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 06/21/2024] [Accepted: 06/24/2024] [Indexed: 07/28/2024] Open
Abstract
Ovarian cancer (OC), known for its lethality and resistance to chemotherapy, is closely associated with iron metabolism and ferroptosis-an iron-dependent cell death process, distinct from both autophagy and apoptosis. Emerging evidence suggests that dysregulation of iron metabolism could play a crucial role in OC by inducing an imbalance in the redox system, which leads to ferroptosis, offering a novel therapeutic approach. This review examines how disruptions in iron metabolism, which affect redox balance, impact OC progression, focusing on its essential cellular functions and potential as a therapeutic target. It highlights the molecular interplay, including the role of non-coding RNAs (ncRNAs), between iron metabolism and ferroptosis, and explores their interactions with key immune cells such as macrophages and T cells, as well as inflammation within the tumor microenvironment. The review also discusses how glycolysis-related iron metabolism influences ferroptosis via reactive oxygen species. Targeting these pathways, especially through agents that modulate iron metabolism and ferroptosis, presents promising therapeutic prospects. The review emphasizes the need for deeper insights into iron metabolism and ferroptosis within the redox-regulated system to enhance OC therapy and advocates for continued research into these mechanisms as potential strategies to combat OC.
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Affiliation(s)
- Dan Liu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital, Yangtze University, Jingzhou 434000, China; (D.L.); (Z.H.)
- Hubei Provincial Clinical Research Center for Personalized Diagnosis and Treatment of Cancer, Jingzhou 434000, China
| | - Zewen Hu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital, Yangtze University, Jingzhou 434000, China; (D.L.); (Z.H.)
- Hubei Provincial Clinical Research Center for Personalized Diagnosis and Treatment of Cancer, Jingzhou 434000, China
| | - Jinzhi Lu
- Hubei Provincial Clinical Research Center for Personalized Diagnosis and Treatment of Cancer, Jingzhou 434000, China
- Department of Laboratory Medicine, The First Affiliated Hospital, Yangtze University, Jingzhou 434000, China
| | - Cunjian Yi
- Department of Obstetrics and Gynecology, The First Affiliated Hospital, Yangtze University, Jingzhou 434000, China; (D.L.); (Z.H.)
- Hubei Provincial Clinical Research Center for Personalized Diagnosis and Treatment of Cancer, Jingzhou 434000, China
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Terzi EM, Possemato R. Iron, Copper, and Selenium: Cancer's Thing for Redox Bling. Cold Spring Harb Perspect Med 2024; 14:a041545. [PMID: 37932129 PMCID: PMC10982729 DOI: 10.1101/cshperspect.a041545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2023]
Abstract
Cells require micronutrients for numerous basic functions. Among these, iron, copper, and selenium are particularly critical for redox metabolism, and their importance is heightened during oncogene-driven perturbations in cancer. In this review, which particularly focuses on iron, we describe how these micronutrients are carefully chaperoned about the body and made available to tissues, a process that is designed to limit the toxicity of free iron and copper or by-products of selenium metabolism. We delineate perturbations in iron metabolism and iron-dependent proteins that are observed in cancer, and describe the current approaches being used to target iron metabolism and iron-dependent processes.
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Affiliation(s)
- Erdem M Terzi
- Department of Pathology, New York University Grossman School of Medicine, New York, New York 10016, USA
- Laura and Isaac Perlmutter Cancer Center, New York, New York 10016, USA
| | - Richard Possemato
- Department of Pathology, New York University Grossman School of Medicine, New York, New York 10016, USA
- Laura and Isaac Perlmutter Cancer Center, New York, New York 10016, USA
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Wang F, Deng G, Liang N, Hu P, Liu K, Liu T, Li Y, Yuan M, Liu L, Xie J, Qiao L, Liu F, Zhang J. Serum ferritin level is an effective prognostic factor for lung cancer immunotherapy. Cancer Biol Ther 2023; 24:2285367. [PMID: 38031846 PMCID: PMC10783829 DOI: 10.1080/15384047.2023.2285367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 11/15/2023] [Indexed: 12/01/2023] Open
Abstract
Immunotherapy of lung cancer has achieved promising clinical results. However, it is urgent to develop predictive biomarkers for effective immunotherapy. While ferroptosis plays a critical role in immunotherapy efficacy, ferritin is an important regulatory factor. We, therefore, hypothesize that basal serum ferritin levels before immunotherapy and their corresponding changes during immunotherapy can be useful predictors of immunotherapy response in patients with lung cancer. We measured serum ferritin levels in 107 patients with lung cancer before and during immune checkpoint blockade treatments and studied the correlation between ferritin levels, response rate, and survival. Moreover, the correlation between basal ferritin and PD-L1 expression, tumor stages and pathological types was also analyzed. Patients with lower basal serum ferritin levels before immunotherapy had longer progression-free survival (PFS) (median 7 vs 4 months, P = .023) and higher disease control rate (DCR) (X2 = 4.837, P = .028), those with downregulated serum ferritin levels during immunotherapy correlated with longer PFS (median 9.5 vs 4 months, P < .001) and higher DCR (X2 = 6.475, P = .011). However, the "integrated factor", which was calculated as the combination of lower basal serum ferritin levels before immunotherapy and downregulated serum ferritin levels during immunotherapy, correlated with prolonged PFS (P < .001). Multivariate analyses revealed that the basal serum ferritin levels before immunotherapy and the corresponding changes during immunotherapy were both strong independent prognostic factors (hazard ratio (HR) = 1.60, P = .041; HR = 2.65, P = .001). These findings suggest that serum ferritin levels can be used as a prognostic biomarker for lung cancer in predicting immunotherapy efficacy.
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Affiliation(s)
- Fei Wang
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- Department of Oncology, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
- Department of Oncology, Zaozhuang Shizhong District People’s Hospital, Zaozhuang, China
| | - Guodong Deng
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Ning Liang
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Pingping Hu
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Kuo Liu
- Department of Clinical Laboratory Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Tong Liu
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- Department of Oncology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, China
| | - Yang Li
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- Department of Oncology, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Meng Yuan
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- Department of Oncology, Shandong Provincial Qianfoshan Hospital, Weifang Medical University, Jinan, China
| | - Li Liu
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- Department of Oncology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, China
| | - Jian Xie
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Lili Qiao
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Fengjun Liu
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Jiandong Zhang
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- Department of Oncology, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
- Department of Oncology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, China
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Qu S, Timmermans AM, Heemskerk-Gerritsen BAM, Trapman-Jansen AMAC, Broeren-Foekens R, Prager-van der Smissen WJC, El Hassnaoui H, van Tienhoven T, Bes-Stobbe CK, Westenend PJ, van Deurzen CHM, Martens JWM, Hooning MJ, Hollestelle A. Expression and Localization of Ferritin-Heavy Chain Predicts Recurrence for Breast Cancer Patients with a BRCA1/2 Mutation. Cancers (Basel) 2023; 16:28. [PMID: 38201455 PMCID: PMC10778040 DOI: 10.3390/cancers16010028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 12/08/2023] [Accepted: 12/15/2023] [Indexed: 01/12/2024] Open
Abstract
The ferritin-heavy chain (FTH1) is the catalytic subunit of the ferroxidase ferritin, which prevents oxidative DNA damage via intracellular iron storage. FTH1 was shown to be a prognostic marker for triple-negative breast cancer (BC) patients and associated with an enrichment of CD8+ effector T cells. However, whether the expression and localization of FTH1 are also associated with clinical outcome in other BC subtypes is unknown. Here, we investigated the association of FTH1 with time to survival in BCs from 222 BRCA1/2 mutation carriers by immunohistochemistry on tissue microarrays. In addition, for 51 of these patients, the association between FTH1 and specific subsets of T cells was evaluated on whole slides using automatic scoring algorithms. We revealed that nuclear FTH1 (nFTH1) expression, in multivariable analyses, was associated with a shorter disease-free (HR = 2.71, 95% CI = 1.49-4.92, p = 0.001) and metastasis-free survival (HR = 3.54, 95% CI = 1.45-8.66, p = 0.006) in patients carrying a BRCA1/2 mutation. However, we found no relation between cytoplasmic FTH1 expression and survival of BRCA1/2 mutation carriers. Moreover, we did not detect an association between FTH1 expression and the amount of CD45+ (p = 0.13), CD8+ (p = 0.18), CD4+ (p = 0.20) or FOXP3+ cells (p = 0.17). Consequently, the mechanism underlying the worse recurrence-free survival of nFTH1 expression in BRCA1/2 mutation carriers needs further investigation.
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Affiliation(s)
- Shuoying Qu
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
| | - A. Mieke Timmermans
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
| | | | - Anita M. A. C. Trapman-Jansen
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
| | - Renée Broeren-Foekens
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
| | | | - Hoesna El Hassnaoui
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
| | - Tim van Tienhoven
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
| | | | | | | | - John W. M. Martens
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
| | - Maartje J. Hooning
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
| | - Antoinette Hollestelle
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
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Al-Rawaf HA, Gabr SA, Iqbal A, Alghadir AH. Circulating microRNAs and hepcidin as predictors of iron homeostasis and anemia among school children: a biochemical and cross-sectional survey analysis. Eur J Med Res 2023; 28:595. [PMID: 38102707 PMCID: PMC10724951 DOI: 10.1186/s40001-023-01579-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 12/07/2023] [Indexed: 12/17/2023] Open
Abstract
BACKGROUND MicroRNAs (miRNAs) can control several biological processes. Thus, the existence of these molecules plays a significant role in regulating human iron metabolism or homeostasis. PURPOSE The study aimed to determine the role of circulating microRNAs and hepcidin in controlling iron homeostasis and evaluating possible anemia among school children. METHODS The study was based on a biochemical and cross-sectional survey study that included three hundred fifty school children aged 12-18 years old. RT-PCR and immunoassay analysis were accomplished to estimate iron concentration, Hgb, serum ferritin (SF), soluble transferrin receptor (sTfR), total body iron stores (TIBs), total oxidative stress (TOS), total antioxidant capacity (TAC), α-1-acid glycoprotein (AGP), high sensitive C-reactive protein (hs-CRP), and miRNAs; miR-146a, miR-129b, and miR-122 in 350 school adolescents. RESULTS Iron disorders were cross-sectionally predicted in 28.54% of the study population; they were classified into 14.26% with ID, 5.7% with IDA, and 8.6% with iron overload. The overall proportion of iron depletion was significantly higher in girls (20.0%) than in boys (8.6%). MicroRNAs; miR-146a, miR-125b, and miR-122 were significantly upregulated with lower hepcidin expression in adolescence with ID and IDA compared to iron-overloaded subjects, whereas downregulation of these miRNAs was linked with higher hepcidin. Also, a significant correlation was recorded between miRNAs, hepcidin levels, AGP, hs-CRP, TAC, and other iron-related indicators. CONCLUSION Molecular microRNAs such as miR-146a, miR-125b, and miR-122 were shown to provide an additional means of controlling or regulating cellular iron uptake or metabolism either via the oxidative stress pathway or regulation of hepcidin expression via activating genes encoding Hfe and Hjv activators, which promote iron regulation. Thus, circulating miRNAs as molecular markers and serum hepcidin could provide an additional means of controlling or regulating cellular iron and be associated as valuable markers in diagnosing and treating cases with different iron deficiencies.
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Affiliation(s)
- Hadeel A Al-Rawaf
- Departments of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
- Rehabilitation Research Chair, Department of Rehabilitation Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Sami A Gabr
- Rehabilitation Research Chair, Department of Rehabilitation Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Amir Iqbal
- Rehabilitation Research Chair, Department of Rehabilitation Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia.
| | - Ahmad H Alghadir
- Rehabilitation Research Chair, Department of Rehabilitation Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
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11
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Wusiman D, Li W, Guo L, Huang Z, Zhang Y, Zhang X, Zhao X, Li L, An Z, Li Z, Ying J, An C. Comprehensive analysis of single-cell and bulk RNA-sequencing data identifies B cell marker genes signature that predicts prognosis and analysis of immune checkpoints expression in head and neck squamous cell carcinoma. Heliyon 2023; 9:e22656. [PMID: 38125461 PMCID: PMC10731009 DOI: 10.1016/j.heliyon.2023.e22656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 11/13/2023] [Accepted: 11/16/2023] [Indexed: 12/23/2023] Open
Abstract
Recent studies have shown that B cells and the associated tertiary lymphoid structures (TLS) correlate with the response of patients to immune checkpoint inhibitors (ICIs) and predict overall survival (OS) in cancer patients. We screened 145 B cell marker genes (BCMG) by a comprehensive analysis of single-cell RNA-sequencing (scRNA-seq) data of head and neck squamous cell carcinoma (HNSC) from the Gene Expression Omnibus (GEO) database. The BCMG signature (BCMGS) was established using The Cancer Genome Atlas (TCGA) dataset of HNSC and verified in four independent datasets. The multivariate Cox regression analysis identified the signature as an independent prognostic factor. A prognostic nomogram was constructed with independent prognostic factors using the TCGA dataset. GO and KEGG analysis revealed the underlying signaling pathways related to this signature. Study of immune profiles showed that patients in the low-risk group presented discriminative immune-cell infiltrations. Furthermore, the low-risk group was featured by higher TCR and BCR diversity, which suggested that low-risk patients may be more sensitive to ICIs. Immunohistochemistry was performed, and we found that high expression of FTH1 was significantly correlated with poor OS (P = 0.025). The expression of TIM-3, LAG-3 and PD-1 was positively correlated and associated with better OS in HNSC. However, there was no statistically significant difference between PD-L1, PD-L2, CTLA-4, TIGIT and prognosis. The BCMGS was a promising prognostic biomarker in HNSC, which may help to interpret the responses to immunotherapy and provide a new perspective for future research on the treatment in HNSC.
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Affiliation(s)
- Dilinaer Wusiman
- Department of Head and Neck Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Wenbin Li
- Department of Pathology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Lei Guo
- Department of Pathology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Zehao Huang
- Department of Head and Neck Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yi Zhang
- Department of Pathology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xiwei Zhang
- Department of Head and Neck Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xiaohui Zhao
- Department of Head and Neck Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Lin Li
- Department of Pathology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Zhaohong An
- Department of Head and Neck Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Zhengjiang Li
- Department of Head and Neck Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Jianming Ying
- Department of Pathology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Changming An
- Department of Head and Neck Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
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12
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Kwantwi LB. Exosome-mediated crosstalk between tumor cells and innate immune cells: implications for cancer progression and therapeutic strategies. J Cancer Res Clin Oncol 2023; 149:9487-9503. [PMID: 37154928 DOI: 10.1007/s00432-023-04833-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 05/02/2023] [Indexed: 05/10/2023]
Abstract
The increasing number of cancer-associated deaths despite the substantial improvement in diagnosis and treatment has sparked discussions on the need for novel biomarkers and therapeutic strategies for cancer. Exosomes have become crucial players in tumor development and progression, largely due to the diverse nature of their cargo content released to recipient cells. Importantly, exosome-mediated crosstalk between tumor and stromal cells is essential in reprogramming the tumor microenvironment to facilitate tumor progression. As a result, exosomes have gradually become a marker for the early diagnosis of many diseases and an important tool in drug delivery systems. However, the precise mechanisms by which exosomes participate in tumor progression remain elusive, multifaceted, and a double-edged sword, thus requiring further clarification. The available evidence suggests that exosomes can facilitate communication between innate immune cells and tumor cells to either support or inhibit tumor progression. Herein, this review focused on exosome-mediated intercellular communication between tumor cells and macrophages, neutrophils, mast cells, monocytes, dendritic cells, and natural killer cells. Specifically, how such intercellular communication affects tumor progression has been described. It has also been discussed that, depending on their cargo, exosomes can suppress or promote tumor cell progression. In addition, the potential application of exosomes and strategies to target exosomes in cancer treatment has been comprehensively discussed.
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Affiliation(s)
- Louis Boafo Kwantwi
- Department of Medical Imaging Sciences, Klintaps College of Health and Allied Sciences, Accra, DTD. TDC, 30A Klagon, Com. 19, Tema, Ghana.
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13
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Ganesan R, Bhasin SS, Bakhtiary M, Krishnan U, Cheemarla NR, Thomas BE, Bhasin MK, Sukhatme VP. Taxane chemotherapy induces stromal injury that leads to breast cancer dormancy escape. PLoS Biol 2023; 21:e3002275. [PMID: 37699010 PMCID: PMC10497165 DOI: 10.1371/journal.pbio.3002275] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 07/24/2023] [Indexed: 09/14/2023] Open
Abstract
A major cause of cancer recurrence following chemotherapy is cancer dormancy escape. Taxane-based chemotherapy is standard of care in breast cancer treatment aimed at killing proliferating cancer cells. Here, we demonstrate that docetaxel injures stromal cells, which release protumor cytokines, IL-6 and granulocyte colony stimulating factor (G-CSF), that in turn invoke dormant cancer outgrowth both in vitro and in vivo. Single-cell transcriptomics shows a reprogramming of awakened cancer cells including several survival cues such as stemness, chemoresistance in a tumor stromal organoid (TSO) model, as well as an altered tumor microenvironment (TME) with augmented protumor immune signaling in a syngeneic mouse breast cancer model. IL-6 plays a role in cancer cell proliferation, whereas G-CSF mediates tumor immunosuppression. Pathways and differential expression analyses confirmed MEK as the key regulatory molecule in cancer cell outgrowth and survival. Antibody targeting of protumor cytokines (IL-6, G-CSF) or inhibition of cytokine signaling via MEK/ERK pathway using selumetinib prior to docetaxel treatment prevented cancer dormancy outgrowth suggesting a novel therapeutic strategy to prevent cancer recurrence.
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Affiliation(s)
- Ramya Ganesan
- Department of Medicine—Renal Division, Emory University School of Medicine, Atlanta, Georgia, United States of America
| | - Swati S. Bhasin
- Department of Pediatrics—Hematology Division, Emory University School of Medicine, Atlanta, Georgia, United States of America
- Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta, Georgia, United States of America
| | - Mojtaba Bakhtiary
- Department of Pediatrics—Hematology Division, Emory University School of Medicine, Atlanta, Georgia, United States of America
- Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta, Georgia, United States of America
| | - Upaasana Krishnan
- Department of Pediatrics—Hematology Division, Emory University School of Medicine, Atlanta, Georgia, United States of America
- Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America
| | - Nagarjuna R. Cheemarla
- Department of Laboratory Medicine, Yale School of Medicine, New Haven, Connecticut, United States of America
- Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut, United States of America
| | - Beena E. Thomas
- Department of Pediatrics—Hematology Division, Emory University School of Medicine, Atlanta, Georgia, United States of America
- Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta, Georgia, United States of America
| | - Manoj K. Bhasin
- Department of Pediatrics—Hematology Division, Emory University School of Medicine, Atlanta, Georgia, United States of America
- Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta, Georgia, United States of America
- Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America
- Department of Biomedical Informatics, Emory University, Atlanta, Georgia, United States of America
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, United States of America
- Winship Cancer Institute, Emory University, Atlanta, Georgia, United States of America
| | - Vikas P. Sukhatme
- Department of Medicine—Renal Division, Emory University School of Medicine, Atlanta, Georgia, United States of America
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, United States of America
- Winship Cancer Institute, Emory University, Atlanta, Georgia, United States of America
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14
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Ren Y, Mao X, Xu H, Dang Q, Weng S, Zhang Y, Chen S, Liu S, Ba Y, Zhou Z, Han X, Liu Z, Zhang G. Ferroptosis and EMT: key targets for combating cancer progression and therapy resistance. Cell Mol Life Sci 2023; 80:263. [PMID: 37598126 PMCID: PMC10439860 DOI: 10.1007/s00018-023-04907-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 07/31/2023] [Accepted: 08/01/2023] [Indexed: 08/21/2023]
Abstract
Iron-dependent lipid peroxidation causes ferroptosis, a form of regulated cell death. Crucial steps in the formation of ferroptosis include the accumulation of ferrous ions (Fe2+) and lipid peroxidation, of which are controlled by glutathione peroxidase 4 (GPX4). Its crucial role in stopping the spread of cancer has been shown by numerous studies undertaken in the last ten years. Epithelial-mesenchymal transition (EMT) is the process by which epithelial cells acquire mesenchymal characteristics. EMT is connected to carcinogenesis, invasiveness, metastasis, and therapeutic resistance in cancer. It is controlled by a range of internal and external signals and changes the phenotype from epithelial to mesenchymal like. Studies have shown that mesenchymal cancer cells tend to be more ferroptotic than their epithelial counterparts. Drug-resistant cancer cells are more easily killed by inducers of ferroptosis when they undergo EMT. Therefore, understanding the interaction between ferroptosis and EMT will help identify novel cancer treatment targets. In-depth discussion is given to the regulation of ferroptosis, the potential application of EMT in the treatment of cancer, and the relationships between ferroptosis, EMT, and signaling pathways associated with tumors. Invasion, metastasis, and inflammation in cancer all include ferroptosis and EMT. The goal of this review is to provide suggestions for future research and practical guidance for applying ferroptosis and EMT in clinical practice.
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Affiliation(s)
- Yuqing Ren
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Xiangrong Mao
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Hui Xu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Qin Dang
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Siyuan Weng
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Yuyuan Zhang
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Shuang Chen
- Center of Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Shutong Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Yuhao Ba
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Zhaokai Zhou
- Department of Pediatric Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Xinwei Han
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
| | - Zaoqu Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
| | - Guojun Zhang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
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15
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Yanatori I, Nishina S, Kishi F, Hino K. Newly uncovered biochemical and functional aspects of ferritin. FASEB J 2023; 37:e23095. [PMID: 37440196 DOI: 10.1096/fj.202300918r] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 06/27/2023] [Accepted: 07/03/2023] [Indexed: 07/14/2023]
Abstract
Iron homeostasis is strictly regulated at both the systemic and cellular levels by complex mechanisms because of its indispensability and toxicity. Among the various iron-regulatory proteins, ferritin is the earliest discovered regulator of iron metabolism and is a molecule that safely retains excess intracellular iron in the cores of its shells. Two types of ferritin, cytosolic ferritin and mitochondrial ferritin (FTMT), have been identified in a range of organisms from plants to humans. FTMT was identified approximately 60 years after the discovery of cytosolic ferritin. Cytosolic ferritin expression is regulated in an iron-responsive manner. Recently, the molecular mechanisms of iron-dependent degradation of cytosolic ferritin or its secretion into serum have been clarified. FTMT, which shares a high degree of sequence homology with cytosolic ferritin, has distinct functions and is regulated in different ways from cytosolic ferritin. Although knowledge of the physiological role of FTMT is still incomplete, recent studies have shed light on the function and regulation of FTMT. The accumulating biological evidence of both ferritins has made it possible to deepen our knowledge about iron metabolism and its significance in diseases. In this review, we discuss the biological properties of both ferritins, focusing on their newly uncovered behaviors.
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Affiliation(s)
- Izumi Yanatori
- Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Sohji Nishina
- Department of Gastroenterology, Kawasaki Medical School, Kurashiki, Japan
| | - Fumio Kishi
- Kenjinkai Healthcare Corporation, Sanyo-Onoda, Japan
| | - Keisuke Hino
- Department of Gastroenterology, Kawasaki Medical School, Kurashiki, Japan
- Digestive Disease Center, Shunan Memorial Hospital, Kudamatsu, Japan
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16
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Lee J, Roh JL. Altered iron metabolism as a target for ferroptosis induction in head and neck cancer. Cell Oncol (Dordr) 2023; 46:801-810. [PMID: 36811720 DOI: 10.1007/s13402-023-00784-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/16/2023] [Indexed: 02/24/2023] Open
Abstract
Iron is a mineral micronutrient essential for survival and vital functions in many biological processes in living organisms. Iron plays a crucial role as a cofactor of iron-sulfur clusters in energy metabolism and biosynthesis by binding with enzymes and transferring electrons to targets. Iron can also impair cellular functions by damaging organelles and nucleic acids by producing free radicals from redox cycling. Iron-catalyzed reaction products can induce active-site mutations in tumorigenesis and cancer progression. However, the boosted pro-oxidant iron form may contribute to cytotoxicity by increasing soluble radicals and highly reactive oxygen species via the Fenton reaction. An increased redox-active labile iron pool is required for tumor growth and metastasis, but the increased cytotoxic lipid radicals also lead to regulated cell death, such as ferroptosis. Therefore, this may be a major target for selectively killing cancer cells. This review intends to understand altered iron metabolism in cancers and discuss iron-related molecular regulators highly associated with iron-induced cytotoxic radical production and ferroptosis induction, focusing on head and neck cancer.
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Affiliation(s)
- Jaewang Lee
- Department of Otorhinolaryngology-Head and Neck Surgery, CHA Bundang Medical Center, CHA University, 13496, Seongnam, Gyeonggi-do, Republic of Korea
- Department of Biomedical Science, General Graduate School, CHA University, Seongnam, Republic of Korea
| | - Jong-Lyel Roh
- Department of Otorhinolaryngology-Head and Neck Surgery, CHA Bundang Medical Center, CHA University, 13496, Seongnam, Gyeonggi-do, Republic of Korea.
- Department of Biomedical Science, General Graduate School, CHA University, Seongnam, Republic of Korea.
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17
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Shesh BP, Connor JR. A novel view of ferritin in cancer. Biochim Biophys Acta Rev Cancer 2023; 1878:188917. [PMID: 37209958 PMCID: PMC10330744 DOI: 10.1016/j.bbcan.2023.188917] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 05/13/2023] [Accepted: 05/13/2023] [Indexed: 05/22/2023]
Abstract
Since its discovery more than 85 years ago, ferritin has principally been known as an iron storage protein. However, new roles, beyond iron storage, are being uncovered. Novel processes involving ferritin such as ferritinophagy and ferroptosis and as a cellular iron delivery protein not only expand our thinking on the range of contributions of this protein but present an opportunity to target these pathways in cancers. The key question we focus on within this review is whether ferritin modulation represents a useful approach for treating cancers. We discussed novel functions and processes of this protein in cancers. We are not limiting this review to cell intrinsic modulation of ferritin in cancers, but also focus on its utility in the trojan horse approach in cancer therapeutics. The novel functions of ferritin as discussed herein realize the multiple roles of ferritin in cell biology that can be probed for therapeutic opportunities and further research.
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Affiliation(s)
| | - James R Connor
- Department of Neurosurgery, Penn State Hershey Medical Center, Hershey, PA, USA.
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18
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Sarkar MS, Mia MM, Amin MA, Hossain MS, Islam MZ. Bioinformatics and network biology approach to identifying type 2 diabetes genes and pathways that influence the progression of breast cancer. Heliyon 2023; 9:e16151. [PMID: 37234659 PMCID: PMC10205526 DOI: 10.1016/j.heliyon.2023.e16151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 04/28/2023] [Accepted: 05/07/2023] [Indexed: 05/28/2023] Open
Abstract
Breast cancer is the second most prevalent malignancy affecting women. Postmenopausal women breast tumor is one of the top causes of death in women, accounting for 23% of cancer cases. Type 2 diabetes, a worldwide pandemic, has been connected to a heightened risk of several malignancies, although its association with breast cancer is still uncertain. In comparison to non-diabetic women, women with T2DM had a 23% elevated likelihood of developing breast cancer. It is difficult to determine causative or genetic susceptibility that connect T2DM and breast cancer. We created a large-scale network-based quantitative approach employing unbiased methods to discover abnormally amplified genes in both T2DM and breast cancer, to solve these issues. We performed transcriptome analysis to uncover identical genetic biomarkers and pathways to clarify the connection between T2DM and breast cancer patients. In this study, two RNA-seq datasets (GSE103001 and GSE86468) from the Gene Expression Omnibus (GEO) are used to identify mutually differentially expressed genes (DEGs) for breast cancer and T2DM, as well as common pathways and prospective medicines. Firstly, 45 shared genes (30 upregulated and 15 downregulated) between T2D and breast cancer were detected. We employed gene ontology and pathway enrichment to characterize prevalent DEGs' molecular processes and signal transduction pathways and observed that T2DM has certain connections to the progression of breast cancer. Using several computational and statistical approaches, we created a protein-protein interactions (PPI) network and revealed hub genes. These hub genes can be potential biomarkers, which may also lead to new therapeutic strategies for investigated diseases. We conducted TF-gene interactions, gene-microRNA interactions, protein-drug interactions, and gene-disease associations to find potential connections between T2DM and breast cancer pathologies. We assume that the potential drugs that emerged from this study could be useful therapeutic values. Researchers, doctors, biotechnologists, and many others may benefit from this research.
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Affiliation(s)
- Md Sumon Sarkar
- Department of Pharmacy, Islamic University, Kushtia-7003, Bangladesh
| | - Md Misor Mia
- Department of Pharmacy, Islamic University, Kushtia-7003, Bangladesh
| | - Md Al Amin
- Department of Computer Science & Engineering, Prime University, Dhaka-1216, Bangladesh
| | - Md Sojib Hossain
- Department of Mathematics, Govt. Bangla College, Dhaka-1216, Bangladesh
| | - Md Zahidul Islam
- Department of Information & Communication Technology, Islamic University, Kushtia-7003, Bangladesh
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19
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Jiang D, Niu C, Mo G, Wang X, Sun Q, An X, Ji C, Ling W, Li L, Zhao H, Han C, Liu H, Hu J, Kang B. Ferritin heavy chain participated in ameliorating 3-nitropropionic acid-induced oxidative stress and apoptosis of goose follicular granulosa cells. Poult Sci 2023; 102:102606. [PMID: 36940654 PMCID: PMC10033315 DOI: 10.1016/j.psj.2023.102606] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 02/13/2023] [Accepted: 02/16/2023] [Indexed: 02/23/2023] Open
Abstract
Oxidative stress is the major culprits responsible for ovarian dysfunction by damaging granulosa cells (GCs). Ferritin heavy chain (FHC) may participate in the regulation of ovarian function by mediating GCs apoptosis. However, the specific regulatory function of FHC in follicular GCs remains unclear. Here, 3-nitropropionic acid (3-NPA) was utilized to establish an oxidative stress model of follicular GCs of Sichuan white geese. To explore the regulatory effects of FHC on oxidative stress and apoptosis of primary GCs in geese by interfering or overexpressing FHC gene. After transfection of siRNA-FHC to GCs for 60 h, the expressions of FHC gene and protein decreased significantly (P < 0.05). After FHC overexpression for 72 h, the expressions of FHC mRNA and protein upregulated considerably (P < 0.05). The activity of GCs was impaired after interfering with FHC and 3-NPA coincubated (P < 0.05). When overexpression of FHC combined with 3-NPA treatment, the activity of GCs was remarkably enhanced (P < 0.05). After interference FHC and 3-NPA treatment, NF-κB and NRF2 gene expression decreased (P < 0.05), the intracellular reactive oxygen species (ROS) level increased greatly (P < 0.05), BCL-2 expression reduced, BAX/BCL-2 ratio intensified (P < 0.05), the mitochondrial membrane potential decreased notably (P < 0.05), and the apoptosis rate of GCs aggravated (P < 0.05). While overexpression of FHC combined with 3-NPA treatment could promote BCL-2 protein expression and reduce BAX/BCL-2 ratio, indicating that FHC regulated the mitochondrial membrane potential and apoptosis of GCs by mediating the expression of BCL-2. Taken together, our research manifested that FHC alleviated the inhibitory effect of 3-NPA on the activity of GCs. FHC knockdown could suppress the expression of NRF2 and NF-κB genes, reduce BCL-2 expression and augment BAX/BCL-2 ratio, contributing to the accumulation of ROS and jeopardizing mitochondrial membrane potential, as well as exacerbating GCs apoptosis.
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Affiliation(s)
- Dongmei Jiang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, PR China; Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, Sichuan Agricultural University, Chengdu, PR China; Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, PR China
| | - Chunyang Niu
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, PR China; Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, Sichuan Agricultural University, Chengdu, PR China; Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, PR China
| | - Guilin Mo
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, PR China
| | - Xin Wang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, PR China; Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, Sichuan Agricultural University, Chengdu, PR China; Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, PR China
| | - Qian Sun
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, PR China; Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, Sichuan Agricultural University, Chengdu, PR China; Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, PR China
| | - Xiaoguang An
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, PR China; Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, Sichuan Agricultural University, Chengdu, PR China; Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, PR China
| | - Chengweng Ji
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, PR China; Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, Sichuan Agricultural University, Chengdu, PR China; Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, PR China
| | - Weikang Ling
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, PR China; Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, Sichuan Agricultural University, Chengdu, PR China; Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, PR China
| | - Liang Li
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, PR China; Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, Sichuan Agricultural University, Chengdu, PR China; Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, PR China
| | - Hua Zhao
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, PR China
| | - Chunchun Han
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, PR China; Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, Sichuan Agricultural University, Chengdu, PR China; Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, PR China
| | - Hehe Liu
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, PR China; Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, Sichuan Agricultural University, Chengdu, PR China; Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, PR China
| | - Jiwei Hu
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, PR China; Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, Sichuan Agricultural University, Chengdu, PR China; Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, PR China
| | - Bo Kang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, PR China; Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, Sichuan Agricultural University, Chengdu, PR China; Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, PR China.
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20
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Yan H, Talty R, Aladelokun O, Bosenberg M, Johnson CH. Ferroptosis in colorectal cancer: a future target? Br J Cancer 2023; 128:1439-1451. [PMID: 36703079 PMCID: PMC10070248 DOI: 10.1038/s41416-023-02149-6] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 01/05/2023] [Accepted: 01/10/2023] [Indexed: 01/27/2023] Open
Abstract
Colorectal cancer (CRC) is the third leading cause of cancer deaths worldwide and is characterised by frequently mutated genes, such as APC, TP53, KRAS and BRAF. The current treatment options of chemotherapy, radiation therapy and surgery are met with challenges such as cancer recurrence, drug resistance, and overt toxicity. CRC therapies exert their efficacy against cancer cells by activating biological pathways that contribute to various forms of regulated cell death (RCD). In 2012, ferroptosis was discovered as an iron-dependent and lipid peroxide-driven form of RCD. Recent studies suggest that therapies which target ferroptosis are promising treatment strategies for CRC. However, a greater understanding of the mechanisms of ferroptosis initiation, propagation, and resistance in CRC is needed. This review provides an overview of recent research in ferroptosis and its potential role as a therapeutic target in CRC. We also propose future research directions that could help to enhance our understanding of ferroptosis in CRC.
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Affiliation(s)
- Hong Yan
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, 06510, USA
| | - Ronan Talty
- Department of Pathology, Yale School of Medicine, New Haven, CT, USA
| | - Oladimeji Aladelokun
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, 06510, USA
| | - Marcus Bosenberg
- Department of Pathology, Yale School of Medicine, New Haven, CT, USA
- Department of Dermatology, Yale School of Medicine, New Haven, CT, USA
- Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
| | - Caroline H Johnson
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, 06510, USA.
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21
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Zhao X, Richardson DR. The role of the NDRG1 in the pathogenesis and treatment of breast cancer. Biochim Biophys Acta Rev Cancer 2023; 1878:188871. [PMID: 36841367 DOI: 10.1016/j.bbcan.2023.188871] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 02/18/2023] [Accepted: 02/19/2023] [Indexed: 02/26/2023]
Abstract
Breast cancer (BC) is the leading cause of cancer death in women. This disease is heterogeneous, with clinical subtypes being estrogen receptor-α (ER-α) positive, having human epidermal growth factor receptor 2 (HER2) overexpression, or being triple-negative for ER-α, progesterone receptor, and HER2 (TNBC). The ER-α positive and HER2 overexpressing tumors can be treated with agents targeting these proteins, including tamoxifen and pertuzumab, respectively. Despite these treatments, resistance and metastasis are problematic, while TNBC is challenging to treat due to the lack of suitable targets. Many studies examining BC and other tumors indicate a role for N-myc downstream-regulated gene-1 (NDRG1) as a metastasis suppressor. The ability of NDRG1 to inhibit metastasis is due, in part, to the inhibition of the initial step in metastasis, namely the epithelial-to-mesenchymal transition. Paradoxically, there are also reports of NDRG1 playing a pro-oncogenic role in BC pathogenesis. The oncogenic effects of NDRG1 in BC have been reported to relate to lipid metabolism or the mTOR signaling pathway. The molecular mechanism(s) of how NDRG1 regulates the activity of multiple signaling pathways remains unclear. Therapeutic strategies that up-regulate NDRG1 have been developed and include agents of the di-2-pyridylketone thiosemicarbazone class. These compounds target oncogenic drivers in BC cells, suppressing the expression of multiple key hormone receptors including ER-α, progesterone receptor, androgen receptor, and prolactin receptor, and can also overcome tamoxifen resistance. Considering the varying role of NDRG1 in BC pathogenesis, further studies are required to examine what subset of BC patients would benefit from pharmacopeia that up-regulate NDRG1.
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Affiliation(s)
- Xiao Zhao
- Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland 4111, Australia
| | - Des R Richardson
- Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland 4111, Australia; Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
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22
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Daou Y, Falabrègue M, Pourzand C, Peyssonnaux C, Edeas M. Host and microbiota derived extracellular vesicles: Crucial players in iron homeostasis. Front Med (Lausanne) 2022; 9:985141. [PMID: 36314015 PMCID: PMC9606470 DOI: 10.3389/fmed.2022.985141] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Accepted: 09/26/2022] [Indexed: 11/23/2022] Open
Abstract
Iron is a double-edged sword. It is vital for all that’s living, yet its deficiency or overload can be fatal. In humans, iron homeostasis is tightly regulated at both cellular and systemic levels. Extracellular vesicles (EVs), now known as major players in cellular communication, potentially play an important role in regulating iron metabolism. The gut microbiota was also recently reported to impact the iron metabolism process and indirectly participate in regulating iron homeostasis, yet there is no proof of whether or not microbiota-derived EVs interfere in this relationship. In this review, we discuss the implication of EVs on iron metabolism and homeostasis. We elaborate on the blooming role of gut microbiota in iron homeostasis while focusing on the possible EVs contribution. We conclude that EVs are extensively involved in the complex iron metabolism process; they carry ferritin and express transferrin receptors. Bone marrow-derived EVs even induce hepcidin expression in β-thalassemia. The gut microbiota, in turn, affects iron homeostasis on the level of iron absorption and possibly macrophage iron recycling, with still no proof of the interference of EVs. This review is the first step toward understanding the multiplex iron metabolism process. Targeting extracellular vesicles and gut microbiota-derived extracellular vesicles will be a huge challenge to treat many diseases related to iron metabolism alteration.
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Affiliation(s)
- Yasmeen Daou
- International Society of Microbiota, Tokyo, Japan
| | - Marion Falabrègue
- INSERM, CNRS, Institut Cochin, Université de Paris, Paris, France,Laboratory of Excellence GR-Ex, Paris, France
| | - Charareh Pourzand
- Department of Life Sciences, University of Bath, Bath, United Kingdom,Medicines Development, Centre for Therapeutic Innovation, University of Bath, Bath, United Kingdom
| | - Carole Peyssonnaux
- INSERM, CNRS, Institut Cochin, Université de Paris, Paris, France,Laboratory of Excellence GR-Ex, Paris, France
| | - Marvin Edeas
- INSERM, CNRS, Institut Cochin, Université de Paris, Paris, France,Laboratory of Excellence GR-Ex, Paris, France,*Correspondence: Marvin Edeas,
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23
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Abedi M, Rahgozar S. Puzzling Out Iron Complications in Cancer Drug Resistance. Crit Rev Oncol Hematol 2022; 178:103772. [PMID: 35914667 DOI: 10.1016/j.critrevonc.2022.103772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 07/23/2022] [Accepted: 07/28/2022] [Indexed: 12/09/2022] Open
Abstract
Iron metabolism are frequently disrupted in cancer. Patients with cancer are prone to anemia and receive transfusions frequently; the condition which results in iron overload, contributing to serious therapeutic complications. Iron is introduced as a carcinogen that may increase tumor growth. However, investigations regarding its impact on response to chemotherapy, particularly the induction of drug resistance are still limited. Here, iron contribution to cell signaling and various molecular mechanisms underlying iron-mediated drug resistance are described. A dual role of this vital element in cancer treatment is also addressed. On one hand, the need to administer iron chelators to surmount iron overload and improve the sensitivity of tumor cells to chemotherapy is discussed. On the other hand, the necessary application of iron as a therapeutic option by iron-oxide nanoparticles or ferroptosis inducers is explained. Authors hope that this paper can help unravel the clinical complications related to iron in cancer therapy.
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Affiliation(s)
- Marjan Abedi
- Department of Cell and Molecular biology & Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran.
| | - Soheila Rahgozar
- Department of Cell and Molecular biology & Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran.
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24
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Regulatory pathways and drugs associated with ferroptosis in tumors. Cell Death Dis 2022; 13:544. [PMID: 35688814 PMCID: PMC9187756 DOI: 10.1038/s41419-022-04927-1] [Citation(s) in RCA: 74] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 05/04/2022] [Accepted: 05/09/2022] [Indexed: 01/21/2023]
Abstract
Ferroptosis is a type of cell death that depends on iron and reactive oxygen species (ROS). The accumulation of iron and lipid peroxidation primarily initiates oxidative membrane damage during ferroptosis. The core molecular mechanism of ferroptosis includes the regulation of oxidation and the balance between damage and antioxidant defense. Tumor cells usually contain a large amount of H2O2, and ferrous/iron ions will react with excessive H2O2 in cells to produce hydroxyl radicals and induce ferroptosis in tumor cells. Here, we reviewed the latest studies on the regulation of ferroptosis in tumor cells and introduced the tumor-related signaling pathways of ferroptosis. We paid particular attention to the role of noncoding RNA, nanomaterials, the role of drugs, and targeted treatment using ferroptosis drugs for mediating the ferroptosis process in tumor cells. Finally, we discussed the currently unresolved problems and future research directions for ferroptosis in tumor cells and the prospects of this emerging field. Therefore, we have attempted to provide a reference for further understanding of the pathogenesis of ferroptosis and proposed new targets for cancer treatment.
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25
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High-Dose Vitamin C for Cancer Therapy. Pharmaceuticals (Basel) 2022; 15:ph15060711. [PMID: 35745630 PMCID: PMC9231292 DOI: 10.3390/ph15060711] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 05/25/2022] [Accepted: 06/01/2022] [Indexed: 12/24/2022] Open
Abstract
In recent years, the idea that Vitamin C (Vit-C) could be utilized as a form of anti-cancer therapy has generated many contradictory arguments. Recent insights into the physiological characteristics of Vit-C, its pharmacokinetics, and results from preclinical reports, however, suggest that high-dose Vit-C could be effectively utilized in the management of various tumor types. Studies have shown that the pharmacological action of Vit-C can attack various processes that cancerous cells use for their growth and development. Here, we discuss the anti-cancer functions of Vit-C, but also the potential for the use of Vit-C as an epigenetic regulator and immunotherapy enhancer. We also provide a short overview of the current state of systems for scavenging reactive oxygen species (ROS), especially in the context of their influencing high-dose Vit-C toxicity for the inhibition of cancer growth. Even though the mechanisms of Vit-C action are promising, they need to be supported with robust randomized and controlled clinical trials. Moreover, upcoming studies should focus on how to define the most suitable cancer patient populations for high-dose Vit-C treatments and develop effective strategies that combine Vit-C with various concurrent cancer treatment regimens.
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26
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Supplementation with High or Low Iron Reduces Colitis Severity in an AOM/DSS Mouse Model. Nutrients 2022; 14:nu14102033. [PMID: 35631174 PMCID: PMC9147005 DOI: 10.3390/nu14102033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 05/03/2022] [Accepted: 05/07/2022] [Indexed: 11/17/2022] Open
Abstract
The relationship between colitis-associated colorectal cancer (CAC) and the dysregulation of iron metabolism has been implicated. However, studies on the influence of dietary iron deficiency on the incidence of CAC are limited. This study investigated the effects of dietary iron deficiency and dietary non-heme iron on CAC development in an azoxymethane/dextran sodium sulfate (AOM/DSS) mouse model. The four-week-old mice were divided into the following groups: iron control (IC; 35 ppm iron/kg) + normal (NOR), IC + AOM/DSS, iron deficient (ID; <5 ppm iron/kg diet) + AOM/DSS, and iron overload (IOL; approximately 2000 ppm iron/kg) + AOM/DSS. The mice were fed the respective diets for 13 weeks, and the AOM/DSS model was established at week five. FTH1 expression increased in the mice’s colons in the IC + AOM/DSS group compared with that observed in the ID and IOL + AOM/DSS groups. The reduced number of colonic tumors in the ID + AOM/DSS and IOL + AOM/DSS groups was accompanied by the downregulated expression of cell proliferation regulators (PCNA, cyclin D1, and c-Myc). Iron overload inhibited the increase in the expression of NF-κB and its downstream inflammatory cytokines (IL-6, TNFα, iNOS, COX2, and IL-1β), likely due to the elevated expression of antioxidant genes (SOD1, TXN, GPX1, GPX4, CAT, HMOX1, and NQO1). ID + AOM/DSS may hinder tumor development in the AOM/DSS model by inhibiting the PI3K/AKT pathway by increasing the expression of Ndrg1. Our study suggests that ID and IOL diets suppress AOM/DSS-induced tumors and that long-term iron deficiency or overload may negate CAC progression.
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27
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Ren P, Wang K, Ma J, Cao X, Zhao J, Zhao C, Guo Y, Ye H. Autoantibody Against Ferritin Light Chain is a Serum Biomarker for the Detection of Liver Cirrhosis but Not Liver Cancer. J Hepatocell Carcinoma 2022; 9:221-232. [PMID: 35378780 PMCID: PMC8976487 DOI: 10.2147/jhc.s352057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 03/18/2022] [Indexed: 11/23/2022] Open
Abstract
Purpose Ferritin is a protein that plays an important role in iron metabolism, it consists of two subunits: heavy chain (FTH) and light chain (FTL). Elevated expression of FTL is observed in multiple malignancies. Recent studies have found that the frequency of circulating autoantibody against FTL (anti-FTL) increased significantly in hepatocellular carcinoma (HCC). The aim of this study is to verify circulating anti-FTL as a biomarker for the early detection of HCC. Patients and Methods A total of 1565 participants were enrolled and assigned to two independent validation cohorts, including 393 HCC patients, 379 liver cirrhosis (LC) patients, 400 chronic hepatitis (CH) patients, and 393 healthy subjects. The concentration of serum anti-FTL was measured by indirect Enzyme-Linked Immunosorbent Assay (ELISA). Kruskal–Wallis test was used to compare anti-FTL concentrations between HCC group and three control groups. Percentile 95 of anti-FTL absorbance value of healthy group was selected as the cut-off value to calculate the positive rate in each group. The area under receiver operating characteristic curve (AUC) was used to quantitatively describe its diagnostic value. Results The median concentration of anti-FTL in HCC patients was higher than that in CH patients and healthy subjects, but there was no difference between HCC patients and LC patients. Further analysis showed that there was no difference between early stage LC, advanced stage LC, Child-Pugh A HCC, Child-Pugh B HCC and Child-Pugh C HCC. The positive rate of anti-FTL was 12.2% (48/393) in HCC, 13.5% (51/379) in LC, 6.3% (25/400) in CH and 5.1% (20/393) in healthy subjects, respectively. The AUC of anti-FTL to distinguish LC from CH or healthy subjects were 0.654 (95% CI: 0.615–0.692) and 0.642 (95% CI: 0.602–0.681), respectively. Conclusion Anti-FTL is not a biomarker for the early diagnosis of HCC due to specificity deficiency, but may be helpful for the early detection of LC.
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Affiliation(s)
- Pengfei Ren
- Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, People’s Republic of China
- Henan Key Laboratory of Molecular Pathology, Zhengzhou, People’s Republic of China
| | - Keyan Wang
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, People’s Republic of China
| | - Jie Ma
- Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, People’s Republic of China
- Henan Key Laboratory of Molecular Pathology, Zhengzhou, People’s Republic of China
| | - Xiaoqin Cao
- Department of Cancer Epidemiology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, People’s Republic of China
| | - Jiuzhou Zhao
- Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, People’s Republic of China
- Henan Key Laboratory of Molecular Pathology, Zhengzhou, People’s Republic of China
| | - Chengzhi Zhao
- Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, People’s Republic of China
- Henan Key Laboratory of Molecular Pathology, Zhengzhou, People’s Republic of China
| | - Yongjun Guo
- Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, People’s Republic of China
- Henan Key Laboratory of Molecular Pathology, Zhengzhou, People’s Republic of China
- Correspondence: Yongjun Guo, Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University, 127 Dongming Road, Zhengzhou, 450008, People’s Republic of China, Fax +86 371 65587506 Email
| | - Hua Ye
- College of Public Health, Zhengzhou University, Zhengzhou, People’s Republic of China
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, People’s Republic of China
- Hua Ye, College of Public Health, Zhengzhou University, 100 Science Avenue, Zhengzhou, 450001, People’s Republic of China, Fax +86 371 67781248, Email
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28
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Lin Q, Shi Y, Liu Z, Mehrpour M, Hamaï A, Gong C. Non-coding RNAs as new autophagy regulators in cancer progression. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166293. [PMID: 34688868 DOI: 10.1016/j.bbadis.2021.166293] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 09/17/2021] [Accepted: 10/10/2021] [Indexed: 12/09/2022]
Abstract
Recent advances highlight that non-coding RNAs (ncRNAs) are emerging as fundamental regulators in various physiological as well as pathological processes by regulating macro-autophagy. Studies have disclosed that macro-autophagy, which is a highly conserved process involving cellular nutrients, components, and recycling of organelles, can be either selective or non-selective and ncRNAs show their regulation on selective autophagy as well as non-selective autophagy. The abnormal expression of ncRNAs will result in the impairment of autophagy and contribute to carcinogenesis and cancer progression by regulating both selective autophagy as well as non-selective autophagy. This review focuses on the regulatory roles of ncRNAs in autophagy and their involvement in cancer which may provide valuable therapeutic targets for cancer management.
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Affiliation(s)
- Qun Lin
- Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Bioland Laboratory, 510005 Guangzhou, China
| | - Yu Shi
- Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Bioland Laboratory, 510005 Guangzhou, China
| | - Zihao Liu
- Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Bioland Laboratory, 510005 Guangzhou, China
| | - Maryam Mehrpour
- Institut Necker-Enfants Malades (INEM), Inserm U1151-CNRS UMR 8253, 75993, Paris, France; Université Paris Descartes-Sorbonne Paris Cité, 75993 Paris, France
| | - Ahmed Hamaï
- Institut Necker-Enfants Malades (INEM), Inserm U1151-CNRS UMR 8253, 75993, Paris, France; Université Paris Descartes-Sorbonne Paris Cité, 75993 Paris, France
| | - Chang Gong
- Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Bioland Laboratory, 510005 Guangzhou, China.
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29
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Guo Q, Li L, Hou S, Yuan Z, Li C, Zhang W, Zheng L, Li X. The Role of Iron in Cancer Progression. Front Oncol 2021; 11:778492. [PMID: 34858857 PMCID: PMC8631356 DOI: 10.3389/fonc.2021.778492] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 10/15/2021] [Indexed: 01/19/2023] Open
Abstract
Iron is an essential trace element for the human body, and its deficiency or excess can induce a variety of biological processes. Plenty of evidences have shown that iron metabolism is closely related to the occurrence and development of tumors. In addition, iron plays an important role in cell death, which is very important for the development of potential strategies for tumor treatment. Here, we reviewed the latest research about iron metabolism disorders in various types of tumors, the functions and properties of iron in ferroptosis and ferritinophagy, and new opportunities for iron-based on treatment methods for tumors, providing more information regarding the prevention and treatment of tumors.
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Affiliation(s)
- Qianqian Guo
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Liwen Li
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Shanshan Hou
- Department of Pharmacy, Zhejiang Pharmaceutical College, Ningbo, China
| | - Ziqiao Yuan
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Chenhui Li
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Wenzhou Zhang
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Lufeng Zheng
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Xiaoman Li
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
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30
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Whitney HM, Drukker K, Edwards A, Papaioannou J, Medved M, Karczmar G, Giger ML. Robustness of radiomic features of benign breast lesions and hormone receptor positive/HER2-negative cancers across DCE-MR magnet strengths. Magn Reson Imaging 2021; 82:111-121. [PMID: 34174331 PMCID: PMC8386988 DOI: 10.1016/j.mri.2021.06.021] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 06/19/2021] [Accepted: 06/21/2021] [Indexed: 02/07/2023]
Abstract
Radiomic features extracted from breast lesion images have shown potential in diagnosis and prognosis of breast cancer. As medical centers transition from 1.5 T to 3.0 T magnetic resonance (MR) imaging, it is beneficial to identify potentially robust radiomic features across field strengths because images acquired at different field strengths could be used in machine learning models. Dynamic contrast-enhanced MR images of benign breast lesions and hormone receptor positive/HER2-negative (HR+/HER2-) breast cancers were acquired retrospectively, yielding 612 unique cases: 150 and 99 benign lesions imaged at 1.5 T and 3.0 T, and 223 and 140 HR+/HER2- cancerous lesions imaged at 1.5 T and 3.0 T, respectively. In addition, an independent set of seven lesions imaged at both field strengths, three benign lesions and four HR+/HER2- cancers, was analyzed separately. Lesions were automatically segmented using a 4D fuzzy c-means method; thirty-eight radiomic features were extracted. Feature value distributions were compared by cancer status and imaging field strength using the Kolmogorov-Smirnov test. Features that did not demonstrate a statistically significant difference were considered to be potentially robust. The area under the receiver operating characteristic curve (AUC), for the task of classifying lesions as benign or HR+/HER2- cancer, was determined for each feature at each field strength. Three features were found to be both potentially robust across field strength and of high classification performance, i.e., AUCs statistically greater than 0.5 in the classification task: one shape feature (irregularity), one texture feature (sum average) and one enhancement variance kinetics features (enhancement variance increasing rate). In the demonstration set of lesions imaged at both field strengths, two of the three potentially robust features showed qualitative agreement across field strength. These findings may contribute to the development of computer-aided diagnosis models that are robust across field strength for this classification task.
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Affiliation(s)
- Heather M Whitney
- Department of Radiology, The University of Chicago, Chicago, IL 60637, United States of America; Department of Physics, Wheaton College, Wheaton, IL 60187, United States of America.
| | - Karen Drukker
- Department of Radiology, The University of Chicago, Chicago, IL 60637, United States of America
| | - Alexandra Edwards
- Department of Radiology, The University of Chicago, Chicago, IL 60637, United States of America
| | - John Papaioannou
- Department of Radiology, The University of Chicago, Chicago, IL 60637, United States of America
| | - Milica Medved
- Department of Radiology, The University of Chicago, Chicago, IL 60637, United States of America
| | - Gregory Karczmar
- Department of Radiology, The University of Chicago, Chicago, IL 60637, United States of America
| | - Maryellen L Giger
- Department of Radiology, The University of Chicago, Chicago, IL 60637, United States of America.
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31
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Zhang L, Zhang J, Jin Y, Yao G, Zhao H, Qiao P, Wu S. Nrf2 Is a Potential Modulator for Orchestrating Iron Homeostasis and Redox Balance in Cancer Cells. Front Cell Dev Biol 2021; 9:728172. [PMID: 34589492 PMCID: PMC8473703 DOI: 10.3389/fcell.2021.728172] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 08/16/2021] [Indexed: 12/16/2022] Open
Abstract
Iron is an essential trace mineral element in almost all living cells and organisms. However, cellular iron metabolism pathways are disturbed in most cancer cell types. Cancer cells have a high demand of iron. To maintain rapid growth and proliferation, cancer cells absorb large amounts of iron by altering expression of iron metabolism related proteins. However, iron can catalyze the production of reactive oxygen species (ROS) through Fenton reaction. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is an important player in the resistance to oxidative damage by inducing the transcription of antioxidant genes. Aberrant activation of Nrf2 is observed in most cancer cell types. It has been revealed that the over-activation of Nrf2 promotes cell proliferation, suppresses cell apoptosis, enhances the self-renewal capability of cancer stem cells, and even increases the chemoresistance and radioresistance of cancer cells. Recently, several genes involving cellular iron homeostasis are identified under the control of Nrf2. Since cancer cells require amounts of iron and Nrf2 plays pivotal roles in oxidative defense and iron metabolism, it is highly probable that Nrf2 is a potential modulator orchestrating iron homeostasis and redox balance in cancer cells. In this hypothesis, we summarize the recent findings of the role of iron and Nrf2 in cancer cells and demonstrate how Nrf2 balances the oxidative stress induced by iron through regulating antioxidant enzymes and iron metabolism. This hypothesis provides new insights into the role of Nrf2 in cancer progression. Since ferroptosis is dependent on lipid peroxide and iron accumulation, Nrf2 inhibition may dramatically increase sensitivity to ferroptosis. The combination of Nrf2 inhibitors with ferroptosis inducers may exert greater efficacy on cancer therapy.
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Affiliation(s)
- Lingyan Zhang
- Institute of Laboratory Animal Science, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Jian Zhang
- Institute of Laboratory Animal Science, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Yuanqing Jin
- Institute of Laboratory Animal Science, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Gang Yao
- Institute of Laboratory Animal Science, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Hai Zhao
- Institute of Laboratory Animal Science, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Penghai Qiao
- Institute of Laboratory Animal Science, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Shuguang Wu
- Institute of Laboratory Animal Science, Guizhou University of Traditional Chinese Medicine, Guiyang, China
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Emerging role of ferroptosis in breast cancer: New dawn for overcoming tumor progression. Pharmacol Ther 2021; 232:107992. [PMID: 34606782 DOI: 10.1016/j.pharmthera.2021.107992] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 09/02/2021] [Accepted: 09/07/2021] [Indexed: 02/08/2023]
Abstract
Breast cancer has become a serious threat to women's health. Cancer progression is mainly derived from resistance to apoptosis induced by procedures or therapies. Therefore, new drugs or models that can overcome apoptosis resistance should be identified. Ferroptosis is a recently identified mode of cell death characterized by excess reactive oxygen species-induced lipid peroxidation. Since ferroptosis is distinct from apoptosis, necrosis and autophagy, its induction successfully eliminates cancer cells that are resistant to other modes of cell death. Therefore, ferroptosis may become a new direction around which to design breast cancer treatment. Unfortunately, the complete appearance of ferroptosis in breast cancer has not yet been fully elucidated. Furthermore, whether ferroptosis inducers can be used in combination with traditional anti- breast cancer drugs is still unknown. Moreover, a summary of ferroptosis in breast cancer progression and therapy is currently not available. In this review, we discuss the roles of ferroptosis-associated modulators glutathione, glutathione peroxidase 4, iron, nuclear factor erythroid-2 related factor-2, superoxide dismutases, lipoxygenase and coenzyme Q in breast cancer. Furthermore, we provide evidence that traditional drugs against breast cancer induce ferroptosis, and that ferroptosis inducers eliminate breast cancer cells. Finally, we put forward prospect of using ferroptosis inducers in breast cancer therapy, and predict possible obstacles and corresponding solutions. This review will deepen our understanding of the relationship between ferroptosis and breast cancer, and provide new insights into breast cancer-related therapeutic strategies.
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Ali A, Shafarin J, Abu Jabal R, Aljabi N, Hamad M, Sualeh Muhammad J, Unnikannan H, Hamad M. Ferritin heavy chain (FTH1) exerts significant antigrowth effects in breast cancer cells by inhibiting the expression of c-MYC. FEBS Open Bio 2021; 11:3101-3114. [PMID: 34551213 PMCID: PMC8564339 DOI: 10.1002/2211-5463.13303] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 08/19/2021] [Accepted: 09/21/2021] [Indexed: 12/24/2022] Open
Abstract
Overexpression of ferritin heavy chain (FTH1) often associates with good prognosis in breast cancer (BCa), particularly in the triple‐negative subtype (triple‐negative breast cancer). However, the mechanism by which FTH1 exerts its possible tumor suppressor effects in BCa is not known. Here, we examined the bearing of FTH1 silencing or overexpression on several aspects of BCa cell growth in vitro. FTH1 silencing promoted cell growth and mammosphere formation, increased c‐MYC expression, and reduced cell sensitivity to chemotherapy. In contrast, FTH1 overexpression inhibited cell growth, decreased c‐MYC expression, and sensitized cancer cells to chemotherapy; silencing of c‐MYC recapitulated the effects of FTH1 overexpression. These findings show for the first time that FTH1 suppresses tumor growth by inhibiting the expression of key oncogenes, such as c‐MYC.
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Affiliation(s)
- Amjad Ali
- Research Institute for Medical and Health SciencesUniversity of SharjahUnited Arab Emirates
| | - Jasmin Shafarin
- Research Institute for Medical and Health SciencesUniversity of SharjahUnited Arab Emirates
| | - Rola Abu Jabal
- Department of Basic Medical SciencesCollege of MedicineUniversity of SharjahUnited Arab Emirates
| | - Nour Aljabi
- Department of Basic Medical SciencesCollege of MedicineUniversity of SharjahUnited Arab Emirates
| | - Mohamad Hamad
- Research Institute for Medical and Health SciencesUniversity of SharjahUnited Arab Emirates
- Department of Medical Laboratory SciencesCollege of Health SciencesUniversity of SharjahUnited Arab Emirates
| | - Jibran Sualeh Muhammad
- Research Institute for Medical and Health SciencesUniversity of SharjahUnited Arab Emirates
- Department of Basic Medical SciencesCollege of MedicineUniversity of SharjahUnited Arab Emirates
| | - Hema Unnikannan
- Research Institute for Medical and Health SciencesUniversity of SharjahUnited Arab Emirates
| | - Mawieh Hamad
- Research Institute for Medical and Health SciencesUniversity of SharjahUnited Arab Emirates
- Department of Medical Laboratory SciencesCollege of Health SciencesUniversity of SharjahUnited Arab Emirates
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Circulating miRNAs and tissue iron overload in transfusion-dependent β-thalassemia major: novel predictors and follow-up guide. Ann Hematol 2021; 100:2909-2917. [PMID: 34432101 DOI: 10.1007/s00277-021-04639-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 08/18/2021] [Indexed: 11/27/2022]
Abstract
Tissue iron overload is a life-threatening scenario in children with transfusion-dependent β-thalassemia major, miRNAs that are involved in iron hemostasis could serve as therapeutic targets for control of iron overload. We aimed to find out the association between three iron-related miRNAs "miR-let-7d, miR-122, and miR-200b" and excess iron in tissues, in transfusion-dependent β-thalassemia major patients. Circulating miRNA expressions are measured in peripheral blood (PB) samples using qPCR of transfusion-dependent (TDT) β-thalassemia patients (n = 140) and normalized to non-transfusion-dependent (NTDT) β-thalassemia (n = 45). Results revealed that plasma expression levels of miR-let-7d and miR-200b were significantly downregulated in TDT patients; however, miR-122 was upregulated. In terms of tissue iron load, aberrant expression of miRNAs was significantly associated with increased-iron accumulation in hepatic and cardiac tissues. We concluded that circulating miRNAs are strong candidates that associate iron hemostasis in transfusion-dependent β-thalassemia major patients. And by extension, targeting miR-let-7d, miR-122, and miR-200 might serve as novel sensitive, specific and non-invasive predictor biomarkers for cellular damage under condition of tissue iron excess.
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Qian L, Xie H, Zhang L, Zhao Q, Lü J, Yu Z. Piwi-Interacting RNAs: A New Class of Regulator in Human Breast Cancer. Front Oncol 2021; 11:695077. [PMID: 34295823 PMCID: PMC8290475 DOI: 10.3389/fonc.2021.695077] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 06/15/2021] [Indexed: 01/17/2023] Open
Abstract
P-element-induced wimpy testis (Piwi)-interacting RNAs (piRNAs) are a class of germline-enriched small non-coding RNA that associate with Piwi family proteins and mostly induce transposon silencing and epigenetic regulation. Emerging evidence indicated the aberrant expression of Piwil proteins and associated piRNAs in multiple types of human cancer including breast cancer. Although the majority of piRNAs in breast cancer remains unclear of the function mainly due to the variety of regulatory mechanisms, the potential of piRNAs serving as biomarkers for cancer diagnosis and prognosis or therapeutic targets for cancer treatment has been demonstrated by in vitro and in vivo studies. Herein we summarized the research progress of oncogenic or tumor suppressing piRNAs and their regulatory mechanisms in regulating human breast cancer, including piR-021285, piR-823, piR-932, piR-36712, piR-016658, piR-016975 and piR-4987. The challenges and perspectives of piRNAs in the field of human cancer were discussed.
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Affiliation(s)
- Lu Qian
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.,Jinzhou Medical University, School of Basic Medical Sciences, Jinzhou, China
| | - Heying Xie
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.,Jinzhou Medical University, School of Basic Medical Sciences, Jinzhou, China
| | - Libo Zhang
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Qian Zhao
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jinhui Lü
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Zuoren Yu
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
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Skrajnowska D, Tokarz A, Makowska J, Bobrowska-Korczak B. Changes in the Mineral Composition of Rat Tissues Induced by Breast Cancer and Dietary Supplementation. In Vivo 2021; 35:259-266. [PMID: 33402472 DOI: 10.21873/invivo.12254] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 10/19/2020] [Accepted: 10/20/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND/AIM The aim of the study was to determine the effect of various diets with zinc or zinc in combination with resveratrol or genistein on mineral contents of the serum, urine, liver, kidney and heart in rats with chemically-induced mammary carcinoma. MATERIALS AND METHODS The manuscript presents the tissues and body fluids content of iron, calcium, zinc, magnesium and copper in control rats or rats treated with 7,12-dimethyl-1,2-benz[a]anthracene to induce mammary carcinogenesis, under four dietary conditions: standard feed, Zn supplemented feed (6.9 mg Zn/ml), Zn and resveratrol (0.2 mg/kg body) supplemented feed, or Zn and genistein (0.2 mg/kg body) supplemented feed. RESULTS The content of calcium and copper highly varied depending on the tissue and the type of dietary supplement (no change for zinc and magnesium). Irrespective of the diet used, the chemical induction of mammary cancer caused a decrease in iron concentration in most samples analysed. Only supplementation of the rats' diet with zinc and genistein induced no changes in iron distribution in the serum, urine, liver, kidney and heart. CONCLUSION Further research using various levels of zinc and genistein in the diet should be conducted to determine how the development and progression of cancer is linked to iron content in cells and its ability to accumulate in tumour tissue.
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Affiliation(s)
| | - Andrzej Tokarz
- Department of Bromatology, Medical University of Warsaw, Warsaw, Poland
| | - Justyna Makowska
- Department of Bromatology, Medical University of Warsaw, Warsaw, Poland
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37
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Plays M, Müller S, Rodriguez R. Chemistry and biology of ferritin. Metallomics 2021; 13:6244244. [PMID: 33881539 PMCID: PMC8083198 DOI: 10.1093/mtomcs/mfab021] [Citation(s) in RCA: 119] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 04/09/2021] [Indexed: 02/07/2023]
Abstract
Iron is an essential element required by cells and has been described as a key player in ferroptosis. Ferritin operates as a fundamental iron storage protein in cells forming multimeric assemblies with crystalline iron cores. We discuss the latest findings on ferritin structure and activity and its link to cell metabolism and ferroptosis. The chemistry of iron, including its oxidation states, is important for its biological functions, its reactivity, and the biology of ferritin. Ferritin can be localized in different cellular compartments and secreted by cells with a variety of functions depending on its spatial context. Here, we discuss how cellular ferritin localization is tightly linked to its function in a tissue-specific manner, and how impairment of iron homeostasis is implicated in diseases, including cancer and coronavirus disease 2019. Ferritin is a potential biomarker and we discuss latest research where it has been employed for imaging purposes and drug delivery.
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Affiliation(s)
- Marina Plays
- Chemical Biology of Cancer Laboratory, Institut Curie, 26 rue d'Ulm, 75005 Paris, France.,Centre national de la recherche scientifique UMR 3666, Paris, France.,Institut national de la santé et de la recherche médicale U1143, Paris, France.,PSL Université Paris, Paris, France
| | - Sebastian Müller
- Chemical Biology of Cancer Laboratory, Institut Curie, 26 rue d'Ulm, 75005 Paris, France.,Centre national de la recherche scientifique UMR 3666, Paris, France.,Institut national de la santé et de la recherche médicale U1143, Paris, France.,PSL Université Paris, Paris, France
| | - Raphaël Rodriguez
- Chemical Biology of Cancer Laboratory, Institut Curie, 26 rue d'Ulm, 75005 Paris, France.,Centre national de la recherche scientifique UMR 3666, Paris, France.,Institut national de la santé et de la recherche médicale U1143, Paris, France.,PSL Université Paris, Paris, France
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38
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Wang H, Cheng Y, Mao C, Liu S, Xiao D, Huang J, Tao Y. Emerging mechanisms and targeted therapy of ferroptosis in cancer. Mol Ther 2021; 29:2185-2208. [PMID: 33794363 DOI: 10.1016/j.ymthe.2021.03.022] [Citation(s) in RCA: 191] [Impact Index Per Article: 47.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Revised: 01/21/2021] [Accepted: 03/25/2021] [Indexed: 12/13/2022] Open
Abstract
Ferroptosis is an iron- and lipid reactive oxygen species (ROS)-dependent form of programmed cell death that is distinct from other forms of regulatory cell death at the morphological, biological, and genetic levels. Emerging evidence suggests critical roles for ferroptosis in cell metabolism, the redox status, and various diseases, such as cancers, nervous system diseases, and ischemia-reperfusion injury, with ferroptosis-related proteins. Ferroptosis is inhibited in diverse cancer types and functions as a dynamic tumor suppressor in cancer development, indicating that the regulation of ferroptosis can be utilized as an interventional target for tumor treatment. Small molecules and nanomaterials that reprogram cancer cells to undergo ferroptosis are considered effective drugs for cancer therapy. Here, we systematically summarize the molecular basis of ferroptosis, the suppressive effect of ferroptosis on tumors, the effect of ferroptosis on cellular metabolism and the tumor microenvironment (TME), and ferroptosis-inducing agents for tumor therapeutics. An understanding of the latest progress in ferroptosis could provide references for proposing new potential targets for the treatment of cancers.
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Affiliation(s)
- Haiyan Wang
- Key Laboratory of Carcinogenesis and Cancer Invasion (Central South University, Ministry of Education), Department of Pathology, Xiangya Hospital, Central South University, Hunan 410078, China; NHC Key Laboratory of Carcinogenesis, Cancer Research Institute and School of Basic Medicine, Central South University, Changsha, Hunan 410078, China
| | - Yan Cheng
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Chao Mao
- Key Laboratory of Carcinogenesis and Cancer Invasion (Central South University, Ministry of Education), Department of Pathology, Xiangya Hospital, Central South University, Hunan 410078, China; NHC Key Laboratory of Carcinogenesis, Cancer Research Institute and School of Basic Medicine, Central South University, Changsha, Hunan 410078, China
| | - Shuang Liu
- Department of Oncology, Institute of Medical Sciences, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
| | - Desheng Xiao
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
| | - Jun Huang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
| | - Yongguang Tao
- Key Laboratory of Carcinogenesis and Cancer Invasion (Central South University, Ministry of Education), Department of Pathology, Xiangya Hospital, Central South University, Hunan 410078, China; NHC Key Laboratory of Carcinogenesis, Cancer Research Institute and School of Basic Medicine, Central South University, Changsha, Hunan 410078, China; Hunan Key Laboratory of Early Diagnosis and Precision Therapy, Department of Thoracic Surgery, Second Xiangya Hospital, Central South University, Changsha 410011, China.
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Autophagy Triggers Tamoxifen Resistance in Human Breast Cancer Cells by Preventing Drug-Induced Lysosomal Damage. Cancers (Basel) 2021; 13:cancers13061252. [PMID: 33809171 PMCID: PMC7999102 DOI: 10.3390/cancers13061252] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Revised: 03/07/2021] [Accepted: 03/08/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Endocrine therapy with tamoxifen or other endocrine drugs represents the standard treatment for estrogen receptor-positive breast cancer. In spite of effectiveness of this therapy, onset of drug resistance worsens the prognosis of about 30% of patients. Autophagy has recently been proposed as a key player of drug resistance, but the underlying mechanisms are not completely understood. In this research, the authors investigate how autophagy triggers drug resistance in breast cancer cells. The results evidence that tamoxifen affects lysosome integrity, which suggests that this effect may contribute to the anticancer activity of this drug. Activation of autophagy and overexpression of iron-binding proteins synergize in protecting the lysosomal compartment, restraining drug effectiveness in breast cancer cells. According to these results, tamoxifen-resistant cells show an increased autophagic flux and overexpress iron-binding proteins. These findings indicate that screening for the level of iron-binding proteins may help to identify patients at risk for developing drug resistance. Abstract Endocrine resistance is a major complication during treatment of estrogen receptor-positive breast cancer. Although autophagy has recently gained increasing consideration among the causative factors, the link between autophagy and endocrine resistance remains elusive. Here, we investigate the autophagy-based mechanisms of tamoxifen resistance in MCF7 cells. Tamoxifen (Tam) triggers autophagy and affects the lysosomal compartment of MCF7 cells, such that activated autophagy supports disposal of tamoxifen-damaged lysosomes by lysophagy. MCF7 cells resistant to 5 µM tamoxifen (MCF7-TamR) have a higher autophagic flux and an enhanced resistance to Tam-induced lysosomal alterations compared to parental cells, which suggests a correlation between the two events. MCF7-TamR cells overexpress messenger RNAs (mRNAs) for metallothionein 2A and ferritin heavy chain, and they are re-sensitized to Tam by inhibition of autophagy. Overexpressing these proteins in parental MCF7 cells protects lysosomes from Tam-induced damage and preserves viability, while inhibiting autophagy abrogates lysosome protection. Consistently, we also demonstrate that other breast cancer cells that overexpress selected mRNAs encoding iron-binding proteins are less sensitive to Tam-induced lysosomal damage when autophagy is activated. Collectively, our data demonstrate that autophagy triggers Tam resistance in breast cancer cells by favoring the lysosomal relocation of overexpressed factors that restrain tamoxifen-induced lysosomal damage.
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Li X, Si W, Li Z, Tian Y, Liu X, Ye S, Huang Z, Ji Y, Zhao C, Hao X, Chen D, Zhu M. miR‑335 promotes ferroptosis by targeting ferritin heavy chain 1 in in vivo and in vitro models of Parkinson's disease. Int J Mol Med 2021; 47:61. [PMID: 33649797 PMCID: PMC7910012 DOI: 10.3892/ijmm.2021.4894] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 02/02/2021] [Indexed: 02/06/2023] Open
Abstract
Parkinson's disease (PD) is a neurodegenerative disease characterized by the selective loss of dopaminergic neurons in the substantia nigra (SN). In a previous study, the authors demonstrated that ferritin heavy chain 1 (FTH1) inhibited ferroptosis in a model of 6-hydroxydopamine (6-OHDA)-induced PD. However, whether and how microRNAs (miRNAs/miRs) modulate FTH1 in PD ferroptosis is not yet well understood. In the present study, in vivo and in vitro models of PD induced by 6-OHDA were established. The results in vivo and in vitro revealed that the levels of the ferroptosis marker protein, glutathione peroxidase 4 (GPX4), and the PD marker protein, tyrosine hydroxylase (TH), were decreased in the model group, associated with a decreased FTH1 expression and the upregulation of miR-335. In both the in vivo and in vitro models, miR-335 mimic led to a lower FTH1 expression, exacerbated ferroptosis and an enhanced PD pathology. The luciferase 3′-untranslated region reporter results identified FTH1 as the direct target of miR-335. The silencing of FTH1 in 6-OHDA-stimulated cells enhanced the effects of miR-335 on ferroptosis and promoted PD pathology. Mechanistically, miR-335 enhanced ferroptosis through the degradation of FTH1 to increase iron release, lipid peroxidation and reactive oxygen species (ROS) accumulation, and to decrease mitochondrial membrane potential (MMP). On the whole, the findings of the present study reveal that miR-335 promotes ferroptosis by targeting FTH1 in in vitro and in vivo models of PD, providing a potential therapeutic target for the treatment of PD.
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Affiliation(s)
- Xinrong Li
- Traditional Chinese Medicine Innovation Research Center, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, Guangdong 518104, P.R. China
| | - Wenwen Si
- Traditional Chinese Medicine Innovation Research Center, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, Guangdong 518104, P.R. China
| | - Zhan Li
- Guangdong Key Laboratory of Orthopedic Technology and Implant Materials, Key Laboratory of Trauma and Tissue Repair of Tropical Area of PLA, Hospital of Orthopedics, General Hospital of Southern Theater Command of PLA, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510010, P.R. China
| | - Ye Tian
- Baoan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Traditional Chinese Medicine, Shenzhen, Guangdong 518101, P.R. China
| | - Xuelei Liu
- Graduate School, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China
| | - Shanyu Ye
- Department of Anatomy, The Research Center of Basic Integrative Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Zifeng Huang
- Traditional Chinese Medicine Innovation Research Center, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, Guangdong 518104, P.R. China
| | - Yichun Ji
- Baoan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Traditional Chinese Medicine, Shenzhen, Guangdong 518101, P.R. China
| | - Caiping Zhao
- Graduate School, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China
| | - Xiaoqian Hao
- Traditional Chinese Medicine Innovation Research Center, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, Guangdong 518104, P.R. China
| | - Dongfeng Chen
- Department of Anatomy, The Research Center of Basic Integrative Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Meiling Zhu
- Traditional Chinese Medicine Innovation Research Center, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, Guangdong 518104, P.R. China
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Tian X, Xu WH, Anwaier A, Wang HK, Wan FN, Cao DL, Luo WJ, Shi GH, Qu YY, Zhang HL, Ye DW. Construction of a robust prognostic model for adult adrenocortical carcinoma: Results from bioinformatics and real-world data. J Cell Mol Med 2021; 25:3898-3911. [PMID: 33626208 PMCID: PMC8051734 DOI: 10.1111/jcmm.16323] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Revised: 12/24/2020] [Accepted: 01/09/2021] [Indexed: 12/27/2022] Open
Abstract
This study aims to construct a robust prognostic model for adult adrenocortical carcinoma (ACC) by large‐scale multiomics analysis and real‐world data. The RPPA data, gene expression profiles and clinical information of adult ACC patients were obtained from The Cancer Proteome Atlas (TCPA), Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). Integrated prognosis‐related proteins (IPRPs) model was constructed. Immunohistochemistry was used to validate the prognostic value of the IPRPs model in Fudan University Shanghai Cancer Center (FUSCC) cohort. 76 ACC cases from TCGA and 22 ACC cases from GSE10927 in NCBI’s GEO database with full data for clinical information and gene expression were utilized to validate the effectiveness of the IPRPs model. Higher FASN (P = .039), FIBRONECTIN (P < .001), TFRC (P < .001), TSC1 (P < .001) expression indicated significantly worse overall survival for adult ACC patients. Risk assessment suggested significantly a strong predictive capacity of IPRPs model for poor overall survival (P < .05). IPRPs model showed a little stronger ability for predicting prognosis than Ki‐67 protein in FUSCC cohort (P = .003, HR = 3.947; P = .005, HR = 3.787). In external validation of IPRPs model using gene expression data, IPRPs model showed strong ability for predicting prognosis in TCGA cohort (P = .005, HR = 3.061) and it exhibited best ability for predicting prognosis in GSE10927 cohort (P = .0898, HR = 2.318). This research constructed IPRPs model for predicting adult ACC patients’ prognosis using proteomic data, gene expression data and real‐world data and this prognostic model showed stronger predictive value than other biomarkers (Ki‐67, Beta‐catenin, etc) in multi‐cohorts.
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Affiliation(s)
- Xi Tian
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wen-Hao Xu
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Aihetaimujiang Anwaier
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hong-Kai Wang
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Fang-Ning Wan
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Da-Long Cao
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wen-Jie Luo
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Guo-Hai Shi
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yuan-Yuan Qu
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hai-Liang Zhang
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Ding-Wei Ye
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
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Shen L, Zhou Y, He H, Chen W, Lenahan C, Li X, Deng Y, Shao A, Huang J. Crosstalk between Macrophages, T Cells, and Iron Metabolism in Tumor Microenvironment. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:8865791. [PMID: 33628389 PMCID: PMC7889336 DOI: 10.1155/2021/8865791] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 09/28/2020] [Accepted: 01/12/2021] [Indexed: 02/06/2023]
Abstract
Leukocytes, including macrophages and T cells, represent key players in the human immune system, which plays a considerable role in the development and progression of tumors by immune surveillance or immune escape. Boosting the recruitment of leukocytes into the tumor microenvironment and promoting their antitumor responses have been hot areas of research in recent years. Although immunotherapy has manifested a certain level of success in some malignancies, the overall effectiveness is far from satisfactory. Iron is an essential trace element required in multiple, normal cellular processes, such as DNA synthesis and repair, cellular respiration, metabolism, and signaling, while dysregulated iron metabolism has been declared one of the metabolic hallmarks of malignant cancer cells. Furthermore, iron is implicated in the modulation of innate and adaptive immune responses, and elucidating the targeted regulation of iron metabolism may have the potential to benefit antitumor immunity and cancer treatment. In the present review, we briefly summarize the roles of leukocytes and iron metabolism in tumorigenesis, as well as their crosstalk in the tumor microenvironment. The combination of immunotherapy with targeted regulation of iron and iron-dependent regulated cell death (ferroptosis) may be a focus of future research.
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Affiliation(s)
- Lesang Shen
- Department of Breast Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310009, China
| | - Yunxiang Zhou
- Department of Surgical Oncology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
| | - Haifei He
- Department of Surgical Oncology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
| | - Wuzhen Chen
- Department of Breast Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310009, China
| | - Cameron Lenahan
- Burrell College of Osteopathic Medicine, Las Cruces, NM, USA
| | - Xiaoyi Li
- Department of Nuclear Medicine and PET-CT Center, The Second Affiliated Hospital, Zhejiang University, Hangzhou 310009, China
| | - Yongchuan Deng
- Department of Surgical Oncology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
| | - Anwen Shao
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
| | - Jian Huang
- Department of Breast Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310009, China
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43
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Zhang N, Yu X, Xie J, Xu H. New Insights into the Role of Ferritin in Iron Homeostasis and Neurodegenerative Diseases. Mol Neurobiol 2021; 58:2812-2823. [PMID: 33507490 DOI: 10.1007/s12035-020-02277-7] [Citation(s) in RCA: 114] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 12/28/2020] [Indexed: 12/11/2022]
Abstract
Growing evidence has indicated that iron deposition is one of the key factors leading to neuronal death in the neurodegenerative diseases. Ferritin is a hollow iron storage protein composed of 24 subunits of two types, ferritin heavy chain (FTH) and ferritin light chain (FTL), which plays an important role in maintaining iron homeostasis. Recently, the discovery of extracellular ferritin and ferritin in exosomes indicates that ferritin might be not only an iron storage protein within the cell, but might also be an important factor in the regulation of tissue and body iron homeostasis. In this review, we first described the structural characteristics, regulation and the physiological functions of ferritin. Secondly, we reviewed the current evidence concerning the mechanisms underlying the secretion of ferritin and the possible role of secreted ferritin in the brain. Then, we summarized the relationship between ferritin and the neurodegenerative diseases including Parkinson's disease (PD), Alzheimer's disease (AD) and neuroferritinopathy (NF). Given the importance and relationship between iron and neurodegenerative diseases, understanding the role of ferritin in the brain can be expected to contribute to our knowledge of iron dysfunction and neurodegenerative diseases.
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Affiliation(s)
- Na Zhang
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, School of Basic Medicine, Qingdao University, Qingdao, 266071, China.,Institute of Brain Science and Disease, Qingdao University, Qingdao, 266071, China
| | - Xiaoqi Yu
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, School of Basic Medicine, Qingdao University, Qingdao, 266071, China.,Institute of Brain Science and Disease, Qingdao University, Qingdao, 266071, China
| | - Junxia Xie
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, School of Basic Medicine, Qingdao University, Qingdao, 266071, China. .,Institute of Brain Science and Disease, Qingdao University, Qingdao, 266071, China.
| | - Huamin Xu
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, School of Basic Medicine, Qingdao University, Qingdao, 266071, China. .,Institute of Brain Science and Disease, Qingdao University, Qingdao, 266071, China.
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44
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Hsu MY, Mina E, Roetto A, Porporato PE. Iron: An Essential Element of Cancer Metabolism. Cells 2020; 9:cells9122591. [PMID: 33287315 PMCID: PMC7761773 DOI: 10.3390/cells9122591] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 11/24/2020] [Accepted: 11/30/2020] [Indexed: 02/06/2023] Open
Abstract
Cancer cells undergo considerable metabolic changes to foster uncontrolled proliferation in a hostile environment characterized by nutrient deprivation, poor vascularization and immune infiltration. While metabolic reprogramming has been recognized as a hallmark of cancer, the role of micronutrients in shaping these adaptations remains scarcely investigated. In particular, the broad electron-transferring abilities of iron make it a versatile cofactor that is involved in a myriad of biochemical reactions vital to cellular homeostasis, including cell respiration and DNA replication. In cancer patients, systemic iron metabolism is commonly altered. Moreover, cancer cells deploy diverse mechanisms to increase iron bioavailability to fuel tumor growth. Although iron itself can readily participate in redox reactions enabling vital processes, its reactivity also gives rise to reactive oxygen species (ROS). Hence, cancer cells further rely on antioxidant mechanisms to withstand such stress. The present review provides an overview of the common alterations of iron metabolism occurring in cancer and the mechanisms through which iron promotes tumor growth.
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Affiliation(s)
- Myriam Y. Hsu
- Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Turin, Italy; (M.Y.H.); (E.M.)
| | - Erica Mina
- Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Turin, Italy; (M.Y.H.); (E.M.)
| | - Antonella Roetto
- Department of Clinical and Biological Science, University of Turin, AOU San Luigi Gonzaga, 10043 Orbassano, Italy
- Correspondence: (A.R.); (P.E.P.)
| | - Paolo E. Porporato
- Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Turin, Italy; (M.Y.H.); (E.M.)
- Correspondence: (A.R.); (P.E.P.)
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45
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Čiburienė E, Čelutkienė J, Aidietienė S, Ščerbickaitė G, Lyon AR. The prevalence of iron deficiency and anemia and their impact on survival in patients at a cardio-oncology clinic. CARDIO-ONCOLOGY 2020; 6:29. [PMID: 33292849 PMCID: PMC7709383 DOI: 10.1186/s40959-020-00086-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 11/19/2020] [Indexed: 11/24/2022]
Abstract
Background Iron deficiency (ID) and anemia are common in both heart failure (HF) and cancer patients and are associated with poor quality of life and survival. The aims of this study were (1) to evaluate the prevalence, types, and confounding factors of ID and anemia in patients referred to cardio-oncology clinic, and (2) identify the association between iron metabolism parameters and survival of cardio-oncology patients. Methods We assessed iron, ferritin, hemoglobin concentrations, transferrin saturation (TSAT), cancer type, brain natriuretic peptide (BNP), left ventricular ejection fraction (LVEF), kidney function, cardiovascular risk factors and survival in 599 patients who were referred to cardio-oncology clinic from 2011 to 2017. ID was defined by a TSAT < 20%, absolute iron deficiency (AID) with a serum ferritin level < 100 μg/L while serum ferritin level of ≥ 100 μg/L was considered as functional iron deficiency (FID) and TSAT ≥ 20% was considered as no ID. Results The prevalence of ID, AID, and FID was 46, 31, and 15% of study patients, respectively. Anemia was present in approximately half (54%) of the patients with any ID. Multivariate Cox analyses showed that male gender (HR 1.704 [1.207–2.404] p = 0.002); previous cancer history (HR 1.879 [1.079–3.272] p = 0.026); elevated BNP (HR 2.126 [1.258–3.590] p = 0.005); TSAT< 20% (HR 1.721 [1.214–2.439] p = 0.002); ferritin ≥ 100 μg/L (HR 2.008 [1.088–3.706] p = 0.026); serum iron concentration < 12 μmol/L (HR 2.292 [1.614–3.255] p < 0.001); FID (HR 2.538 [1.1618–3.981] p < 0.001) and anemia (HR 2.462 [1.734–3.495] p < 0.001) were significantly associated with increased risk of all-cause death. Conclusions About half of cardio-oncology patients had anemia and iron deficiency, with the absolute type being twice as prevalent as the functional one. Patients with breast, gastrointestinal, and genitourinary cancer were affected more often. Both anemia and iron deficiency independently predicted all-cause mortality. Future studies are required to confirm ID as a risk factor and evaluate the clinical benefits of iron replacement therapy.
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Affiliation(s)
- E Čiburienė
- Clinic of Cardiac and Vascular Diseases, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, M.K.Čiurlionis str. 21, 03101, Vilnius, Lithuania.
| | - J Čelutkienė
- Clinic of Cardiac and Vascular Diseases, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, M.K.Čiurlionis str. 21, 03101, Vilnius, Lithuania
| | - S Aidietienė
- Clinic of Cardiac and Vascular Diseases, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, M.K.Čiurlionis str. 21, 03101, Vilnius, Lithuania
| | - G Ščerbickaitė
- Clinic of Cardiac and Vascular Diseases, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, M.K.Čiurlionis str. 21, 03101, Vilnius, Lithuania
| | - A R Lyon
- Cardio-Oncology Clinic at Royal Brompton Hospital, London, UK.,Imperial College London, London, UK
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Di Sanzo M, Quaresima B, Biamonte F, Palmieri C, Faniello MC. FTH1 Pseudogenes in Cancer and Cell Metabolism. Cells 2020; 9:E2554. [PMID: 33260500 PMCID: PMC7760355 DOI: 10.3390/cells9122554] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 11/24/2020] [Accepted: 11/24/2020] [Indexed: 12/15/2022] Open
Abstract
Ferritin, the principal intracellular iron-storage protein localized in the cytoplasm, nucleus, and mitochondria, plays a major role in iron metabolism. The encoding ferritin genes are members of a multigene family that includes some pseudogenes. Even though pseudogenes have been initially considered as relics of ancient genes or junk DNA devoid of function, their role in controlling gene expression in normal and transformed cells has recently been re-evaluated. Numerous studies have revealed that some pseudogenes compete with their parental gene for binding to the microRNAs (miRNAs), while others generate small interference RNAs (siRNAs) to decrease functional gene expression, and still others encode functional mutated proteins. Consequently, pseudogenes can be considered as actual master regulators of numerous biological processes. Here, we provide a detailed classification and description of the structural features of the ferritin pseudogenes known to date and review the recent evidence on their mutual interrelation within the complex regulatory network of the ferritin gene family.
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Affiliation(s)
- Maddalena Di Sanzo
- Department of Experimental and Clinical Medicine, “Magna Graecia” University of Catanzaro, 88100 Catanzaro, Italy; (M.D.S.); (B.Q.); (F.B.)
| | - Barbara Quaresima
- Department of Experimental and Clinical Medicine, “Magna Graecia” University of Catanzaro, 88100 Catanzaro, Italy; (M.D.S.); (B.Q.); (F.B.)
| | - Flavia Biamonte
- Department of Experimental and Clinical Medicine, “Magna Graecia” University of Catanzaro, 88100 Catanzaro, Italy; (M.D.S.); (B.Q.); (F.B.)
| | - Camillo Palmieri
- Department of Experimental and Clinical Medicine, “Magna Graecia” University of Catanzaro, 88100 Catanzaro, Italy; (M.D.S.); (B.Q.); (F.B.)
| | - Maria Concetta Faniello
- Department of Experimental and Clinical Medicine, “Magna Graecia” University of Catanzaro, 88100 Catanzaro, Italy; (M.D.S.); (B.Q.); (F.B.)
- Research Center of Biochemistry and Advanced Molecular Biology, Department of Experimental and Clinical Medicine, “Magna Graecia” University of Catanzaro, 88100 Catanzaro, Italy
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Iron Dysregulation in Human Cancer: Altered Metabolism, Biomarkers for Diagnosis, Prognosis, Monitoring and Rationale for Therapy. Cancers (Basel) 2020; 12:cancers12123524. [PMID: 33255972 PMCID: PMC7761132 DOI: 10.3390/cancers12123524] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 11/21/2020] [Accepted: 11/24/2020] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Iron is the more abundant metal ion in humans. It is essential for life as it has a role in various cellular processes involved, for instance, in cell metabolism and DNA synthesis. These functions are crucial for cell proliferation, and it is therefore not surprising that iron is accumulated in tumors. In this review, we describe normal and altered iron homeostasis mechanisms. We also provide a vision of iron-related proteins with altered expression in cancers and discuss their potential as diagnostic and/or prognostic biomarkers. Finally, we give an overview of therapeutic strategies acting on iron metabolism to fight against cancers. Abstract Iron (Fe) is a trace element that plays essential roles in various biological processes such as DNA synthesis and repair, as well as cellular energy production and oxygen transport, and it is currently widely recognized that iron homeostasis is dysregulated in many cancers. Indeed, several iron homeostasis proteins may be responsible for malignant tumor initiation, proliferation, and for the metastatic spread of tumors. A large number of studies demonstrated the potential clinical value of utilizing these deregulated proteins as prognostic and/or predictive biomarkers of malignancy and/or response to anticancer treatments. Additionally, the iron present in cancer cells and the importance of iron in ferroptosis cell death signaling pathways prompted the development of therapeutic strategies against advanced stage or resistant cancers. In this review, we select relevant and promising studies in the field of iron metabolism in cancer research and clinical oncology. Besides this, we discuss some co-existing discrepant findings. We also present and discuss the latest lines of research related to targeting iron, or its regulatory pathways, as potential promising anticancer strategies for human therapy. Iron chelators, such as deferoxamine or iron-oxide-based nanoparticles, which are already tested in clinical trials, alone or in combination with chemotherapy, are also reported.
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48
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Li Z, Chen L, Chen C, Zhou Y, Hu D, Yang J, Chen Y, Zhuo W, Mao M, Zhang X, Xu L, Wang L, Zhou J. Targeting ferroptosis in breast cancer. Biomark Res 2020; 8:58. [PMID: 33292585 PMCID: PMC7643412 DOI: 10.1186/s40364-020-00230-3] [Citation(s) in RCA: 124] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 09/23/2020] [Indexed: 02/06/2023] Open
Abstract
Ferroptosis is a recently discovered distinct type of regulated cell death caused by the accumulation of lipid-based ROS. Metabolism and expression of specific genes affect the occurrence of ferroptosis, making it a promising therapeutic target to manage cancer. Here, we describe the current status of ferroptosis studies in breast cancer and trace the key regulators of ferroptosis back to previous studies. We also compare ferroptosis to common regulated cell death patterns and discuss the sensitivity to ferroptosis in different subtypes of breast cancer. We propose that viewing ferroptosis-related studies from a historical angle will accelerate the development of ferroptosis-based biomarkers and therapeutic strategies in breast cancer.
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Affiliation(s)
- Zhaoqing Li
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000 Zhejiang China
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), 2nd Affiliated Hospital, School of Medicine, Zhejiang University, 310009 Hangzhou, Zhejiang China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, 310000 Hangzhou, Zhejiang China
| | - Lini Chen
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000 Zhejiang China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, 310000 Hangzhou, Zhejiang China
| | - Cong Chen
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000 Zhejiang China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, 310000 Hangzhou, Zhejiang China
| | - Yulu Zhou
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000 Zhejiang China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, 310000 Hangzhou, Zhejiang China
| | - Dengdi Hu
- Cixi People’s Hospital Medical and Health Group, 315300 Ningbo, Zhejiang China
| | - Jingjing Yang
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000 Zhejiang China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, 310000 Hangzhou, Zhejiang China
| | - Yongxia Chen
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000 Zhejiang China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, 310000 Hangzhou, Zhejiang China
| | - Wenying Zhuo
- Cixi People’s Hospital Medical and Health Group, 315300 Ningbo, Zhejiang China
| | - Misha Mao
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000 Zhejiang China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, 310000 Hangzhou, Zhejiang China
| | - Xun Zhang
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000 Zhejiang China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, 310000 Hangzhou, Zhejiang China
| | - Ling Xu
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000 Zhejiang China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, 310000 Hangzhou, Zhejiang China
| | - Linbo Wang
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000 Zhejiang China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, 310000 Hangzhou, Zhejiang China
| | - Jichun Zhou
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000 Zhejiang China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, 310000 Hangzhou, Zhejiang China
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Bae DH, Gholam Azad M, Kalinowski DS, Lane DJR, Jansson PJ, Richardson DR. Ascorbate and Tumor Cell Iron Metabolism: The Evolving Story and Its Link to Pathology. Antioxid Redox Signal 2020; 33:816-838. [PMID: 31672021 DOI: 10.1089/ars.2019.7903] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Significance: Vitamin C or ascorbate (Asc) is a water-soluble vitamin and an antioxidant that is involved in many crucial biological functions. Asc's ability to reduce metals makes it an essential enzyme cofactor. Recent Advances: The ability of Asc to act as a reductant also plays an important part in its overall role in iron metabolism, where Asc induces both nontransferrin-bound iron and transferrin-bound iron uptake at physiological concentrations (∼50 μM). Moreover, Asc has emerged to play an important role in multiple diseases and its effects at pharmacological doses could be important for their treatment. Critical Issues: Asc's role as a regulator of cellular iron metabolism, along with its cytotoxic effects and different roles at pharmacological concentrations, makes it a candidate as an anticancer agent. Ever since the controversy regarding the studies from the Mayo Clinic was finally explained, there has been a renewed interest in using Asc as a therapeutic approach toward cancer due to its minimal side effects. Numerous studies have been able to demonstrate the anticancer activity of Asc through selective oxidative stress toward cancer cells via H2O2 generation at pharmacological concentrations. Studies have demonstrated that Asc's cytotoxic mechanism at concentrations (>1 mM) has been associated with decreased cellular iron uptake. Future Directions: Recent studies have also suggested other mechanisms, such as Asc's effects on autophagy, polyamine metabolism, and the cell cycle. Clearly, more has yet to be discovered about Asc's mechanism of action to facilitate safe and effective treatment options for cancer and other diseases.
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Affiliation(s)
- Dong-Hun Bae
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney, Sydney, Australia
| | - Mahan Gholam Azad
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney, Sydney, Australia
| | - Danuta S Kalinowski
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney, Sydney, Australia
| | - Darius J R Lane
- The Florey Institute of Neuroscience and Mental Health, Melbourne Dementia Research Centre, The University of Melbourne, Parkville, Australia
| | - Patric J Jansson
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney, Sydney, Australia
| | - Des R Richardson
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney, Sydney, Australia.,Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Showa-ku, Japan
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50
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Mancinelli R, Cutone A, Rosa L, Lepanto MS, Onori P, Pannarale L, Franchitto A, Gaudio E, Valenti P. Different iron-handling in inflamed small and large cholangiocytes and in small and large-duct type intrahepatic cholangiocarcinoma. Eur J Histochem 2020; 64. [PMID: 33131269 PMCID: PMC7586138 DOI: 10.4081/ejh.2020.3156] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 09/14/2020] [Indexed: 12/15/2022] Open
Abstract
Cholangiocarcinoma (CCA) represents the second most common primary hepatic malignancy and originates from the neoplastic transformation of the biliary cells. The intrahepatic subtype includes two morpho-molecular forms: large-duct type intrahepatic CCA (iCCA) and small-duct type iCCA. Iron is fundamental for the cellular processes, contributing in tumor development and progression. The aim of this study was to evaluate iron uptake, storage, and efflux proteins in both lipopolysaccharide-inflamed small and large cholangiocytes as well as in different iCCA subtypes. Our results show that, despite an increase in interleukin-6 production by both small and large cholangiocytes, ferroportin (Fpn) was decreased only in small cholangiocytes, whereas transferrin receptor-1 (TfR1) and ferritin (Ftn) did not show any change. Differently from in vitro models, Fpn expression was increased in malignant cholangiocytes of small-duct type iCCA in comparison to large-duct type iCCA and peritumoral tissues. TfR1, Ftn and hepcidin were enhanced, even if at different extent, in both malignant cholangiocytes in comparison to the surrounding samples. Lactoferrin was higher in large-duct type iCCA in respect to small-duct type iCCA and peritumoral tissues. These findings show a different iron handling by inflamed small and large cholangiocytes, and small and large-duct type iCCA. The difference in iron homeostasis by the iCCA subtypes may have implications for the tumor management.
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Affiliation(s)
- Romina Mancinelli
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome.
| | - Antimo Cutone
- Department of Biosciences and Territory, University of Molise, Pesche (IS).
| | - Luigi Rosa
- Department of Public Health and Infectious Diseases, Sapienza University of Rome.
| | | | - Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome .
| | - Luigi Pannarale
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome .
| | - Antonio Franchitto
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome; Eleonora Lorillard Spencer Cenci Foundation, Rome.
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome .
| | - Piera Valenti
- Department of Public Health and Infectious Diseases, Sapienza University of Rome.
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