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Zhan J, Chen Y, Liu Y, Chen Y, Li Z, Li X, He Z, Meng F, Qian X, Yang L, Yang Q. IDO1-mediated AhR activation up-regulates pentose phosphate pathway via NRF2 to inhibit ferroptosis in lung cancer. Biochem Pharmacol 2025; 236:116913. [PMID: 40164341 DOI: 10.1016/j.bcp.2025.116913] [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: 01/08/2025] [Revised: 02/28/2025] [Accepted: 03/26/2025] [Indexed: 04/02/2025]
Abstract
Ferroptosis is a type of cell death marked by iron-dependent lipid peroxide accumulation. Indoleamine 2,3-dioxygenase 1 (IDO1), a key enzyme in the catabolism of tryptophan through kynurenine pathway, participates in the development of multiple tumor types. However, the role of IDO1 in tumor ferroptosis is unclear. In this study, we identified IDO1 as a key regulator of ferroptosis in lung cancer. With Erastin-treated lung cancer cells, we found that IDO1 inhibited ferroptosis, reduced the generation of lipid peroxide and ROS. Mechanistically, IDO1 promoted the expression of nuclear factor erythroid 2-related factor 2 (NRF2) through activating aryl hydrocarbon receptor (AhR) pathway. IDO1 up-regulated the expression of solute carrier family 7 member 11 (SLC7A11) and the activity of pentose phosphate pathway (PPP) via AhR-NRF2 axis, promoted the production of reduced nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH), thereby inhibiting ferroptosis. Moreover, combined treatment with IDO1 inhibitor and Erastin inhibited tumor growth, down-regulated SLC7A11 expression and PPP activity, promoted tumor ferroptosis in lung cancer-bearing mice. In conclusion, this study revealed the function of IDO1 in lung cancer ferroptosis and provided a new strategy for lung cancer therapy.
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Affiliation(s)
- Jiani Zhan
- State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, MOE Engineering Research Center of Gene Technology, Shanghai Engineering Research Center of Industrial Microorganisms, Fudan University, Shanghai, China
| | - Yijia Chen
- State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, MOE Engineering Research Center of Gene Technology, Shanghai Engineering Research Center of Industrial Microorganisms, Fudan University, Shanghai, China
| | - Yuying Liu
- State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, MOE Engineering Research Center of Gene Technology, Shanghai Engineering Research Center of Industrial Microorganisms, Fudan University, Shanghai, China
| | - Yunqiu Chen
- State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, MOE Engineering Research Center of Gene Technology, Shanghai Engineering Research Center of Industrial Microorganisms, Fudan University, Shanghai, China
| | - Zhiyao Li
- State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, MOE Engineering Research Center of Gene Technology, Shanghai Engineering Research Center of Industrial Microorganisms, Fudan University, Shanghai, China
| | - Xuewen Li
- State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, MOE Engineering Research Center of Gene Technology, Shanghai Engineering Research Center of Industrial Microorganisms, Fudan University, Shanghai, China
| | - Zhenning He
- State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, MOE Engineering Research Center of Gene Technology, Shanghai Engineering Research Center of Industrial Microorganisms, Fudan University, Shanghai, China
| | - Fangzhou Meng
- State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, MOE Engineering Research Center of Gene Technology, Shanghai Engineering Research Center of Industrial Microorganisms, Fudan University, Shanghai, China
| | - Xiaoyang Qian
- State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, MOE Engineering Research Center of Gene Technology, Shanghai Engineering Research Center of Industrial Microorganisms, Fudan University, Shanghai, China
| | - Lili Yang
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.
| | - Qing Yang
- State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, MOE Engineering Research Center of Gene Technology, Shanghai Engineering Research Center of Industrial Microorganisms, Fudan University, Shanghai, China.
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Schwenk L, Wolf C, Dondorf F, Rohland O, Ali-Deeb A, Settmacher U, Rauchfuß F. The impact of serum ferritin on overall survival following resection in patients with intrahepatic cholangiocarcinoma. Langenbecks Arch Surg 2025; 410:166. [PMID: 40397178 PMCID: PMC12095454 DOI: 10.1007/s00423-025-03737-1] [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: 01/12/2025] [Accepted: 05/09/2025] [Indexed: 05/22/2025]
Abstract
PURPOSE The global incidence of intrahepatic cholangiocarcinoma is increasing. Surgical resection remains the gold standard treatment. However, the long-term prognosis remains dismal. The role of serum ferritin in malignant diseases has not been fully elucidated. This study aimed to evaluate the relationship between preoperative serum ferritin levels and patient outcomes. METHODS In our retrospective study, we analyzed data from 95 patients who underwent liver resection for intrahepatic cholangiocarcinoma at Jena University Hospital between 2009 and 2023. Comprehensive clinical and pathological data, along with the correlation between Serum ferritin and clinicopathological parameters, were systematically analyzed and compared. Survival rates were determined using the Kaplan-Meier method. RESULTS The optimal preoperative serum ferritin cut-off value for overall survival was 303.1 µg/L, with an area under the curve of 0.697 (95% CI (0.592-0.801; P < 0.001). The 1-, 3-, and 5-year survival rates were 74.7%, 50.5%, and 43.2%, respectively. Patients with elevated preoperative SF levels demonstrated significantly worse overall survival compared to the low SF group (50.9% vs. 4.5%; P < 0.001). SF had a significant impact on recurrence rates (P < 0.001). The overall recurrence rate in the high-SF group was 67,3%, compared to 43,5% in the low-SF group. CONCLUSION Elevated preoperative serum ferritin levels are associated with significantly worse overall and recurrence-free survival in patients with intrahepatic cholangiocarcinoma. Serum ferritin could serve as a valuable adjunct to the tumor marker CA 19 - 9.
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Affiliation(s)
- Laura Schwenk
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, Am Klinikum 1, 07740, Jena, Germany.
- Comprehensive Cancer Center Central Germany- Campus Jena, Jena, Germany.
| | - Carlos Wolf
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, Am Klinikum 1, 07740, Jena, Germany
| | - Felix Dondorf
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, Am Klinikum 1, 07740, Jena, Germany
- Comprehensive Cancer Center Central Germany- Campus Jena, Jena, Germany
| | - Oliver Rohland
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, Am Klinikum 1, 07740, Jena, Germany
- Comprehensive Cancer Center Central Germany- Campus Jena, Jena, Germany
- Interdisciplinary Center for Clinical Research (IZKF), Jena University Hospital, Jena, Germany
| | - Aladdin Ali-Deeb
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, Am Klinikum 1, 07740, Jena, Germany
- Comprehensive Cancer Center Central Germany- Campus Jena, Jena, Germany
| | - Utz Settmacher
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, Am Klinikum 1, 07740, Jena, Germany
- Comprehensive Cancer Center Central Germany- Campus Jena, Jena, Germany
| | - Falk Rauchfuß
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, Am Klinikum 1, 07740, Jena, Germany
- Comprehensive Cancer Center Central Germany- Campus Jena, Jena, Germany
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Rondan MA, Sánchez-Hernández A, Estellés DL, Sánchez JG, Aparisi FDAA, López JS, Benajes RT, Sarrió RG. Impact of a comprehensive geriatric assessment to manage elderly patients with locally advanced non-small-cell lung cancers: a multicenter prospective study. Clin Transl Oncol 2025; 27:1039-1046. [PMID: 39158803 DOI: 10.1007/s12094-024-03657-4] [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: 02/28/2024] [Accepted: 07/20/2024] [Indexed: 08/20/2024]
Abstract
PURPOSE Concurrent chemoradiotherapy (cCRT) is the standard treatment for locally advanced and unresectable non-small-cell lung cancer. Population is aging, and Geriatric assessment (GA) has demonstrated its paper to select fit patients for active treatment and vulnerable, frail patients for interventions and/or palliative care in many histologies. Its role in locally advanced, unresectable non-small-cell lung cancer has been less explored. METHODS To assess the capability of GA to detect frail patients not suitable for active treatment, we developed this exploratory non-interventional prospective study. All patients ≥ 70 years diagnosed with stage locally advanced and unresectable non-small-cell lung cancer were invited to undergo geriatric assessment. Secondary aims were description of population, exploring GA as prognostic factor, determination of toxicity profile and look for a frailty biomarker. RESULTS From June 2017 to June 2020, 51 patients were included, of whom 35% (n:18) were classified as frail. Frail patients had less overall survival and more grade 3-4 toxicity. Exploratory results for frailty phenotype are described in the text. CONCLUSIONS With the results of our study, we confirm that GA can detect frail patients unsuitable for treatment, with a higher risk of toxicity and less overall survival. A trend toward blood-test results for phenotype frailty can be hypothesis generation.
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Affiliation(s)
| | | | | | | | | | - Jorge Soler López
- Consorcio Hospital Provincial Castellón, Castellón de la Plana, Spain
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Szymulewska-Konopko K, Reszeć-Giełażyn J, Małeczek M. Ferritin as an Effective Prognostic Factor and Potential Cancer Biomarker. Curr Issues Mol Biol 2025; 47:60. [PMID: 39852175 PMCID: PMC11763953 DOI: 10.3390/cimb47010060] [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: 12/10/2024] [Revised: 01/05/2025] [Accepted: 01/13/2025] [Indexed: 01/26/2025] Open
Abstract
Ferritin is found in all cells of the body, serving as a reservoir of iron and protecting against damage to the molecules that make up cellular structures. It has emerged as a biomarker not only for iron-related disorders but also for inflammatory diseases and conditions in which inflammation plays a key role, including cancer, neurodegeneration, and infection. Oxidative stress, which can cause cellular damage, is induced by reactive oxygen species generated during the Fenton reaction, activating signaling pathways associated with tumor growth and proliferation. This review primarily emphasizes basic studies on the identification and function of ferritin, its essential role in iron metabolism, its involvement in inflammatory diseases, and its potential as an important prognostic factor and biomarker for cancer detection.
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Affiliation(s)
| | - Joanna Reszeć-Giełażyn
- Department of Medical Pathomorphology, Medical University of Bialystok, 15-089 Białystok, Poland; (K.S.-K.); (M.M.)
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Si Q, Wang Y, Lu W, Liu Z, Song Y, Chen S, Xia S, Li H, Weng P, Jing Y, Yu Q, Zhu F, Zhang X, Huang X, Ni Y. Transferrin receptor uptakes iron from tumor-associated neutrophils to regulate invasion patterns of OSCC. Cancer Immunol Immunother 2025; 74:43. [PMID: 39751915 PMCID: PMC11699170 DOI: 10.1007/s00262-024-03894-0] [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: 08/19/2024] [Accepted: 11/13/2024] [Indexed: 01/04/2025]
Abstract
BACKGROUND Transferrin receptor (TFRC) uptakes iron-loaded transferrin (TF) to acquire iron and regulates tumor development. Nonetheless, the clinical values and the precise functions of TF-TFRC axis in the development of oral squamous cell carcinoma (OSCC) were still undiscovered, especially the impacts of their regional heterogeneous expression. METHODS Immunohistochemistry (IHC) was used to analyze the expression of TFRC in 106 OSCC patients. Then the prognostic value of TFRC was compared between high and low worst pattern of invasion (WPOI) patients. OSCC cells with low or high expression of TFRC were constructed, and functional experiments were performed to elucidate the effects of TFRC on the migration and proliferation of OSCC cells. Multi-immunofluorescence was applied to stain TF and tumor-associated neutrophils (TANs). The stimulating effects of TF were compared between normal and high TFRC cells in vitro and across different OSCC patients' subgroups in our sample bank and TCGA database. RESULTS Higher TFRC was expressed at invasive tumor front (ITF) in OSCC and correlated with WPOI. Only at ITF in patients with WPOI 4-5, TFRC was a prognostic factor. High TFRC promoted migration and proliferation of cancer cells. Additionally, TANs secreted TF outside. Exogenous TF promoted migration and proliferation of cells with high expression of TFRC. Compared to the TANslowTFRClow OSCC patients, TANshighTFRChigh OSCC patients had poorer clinical outcomes. CONCLUSIONS Higher expression of TFRC at ITF and TANs-TF-TFRC axis promoted OSCC invasion at ITF by facilitating cell migration and proliferation, which may result from increased cellular iron uptake through regulating iron metabolism.
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Affiliation(s)
- Qian Si
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, China
- Department of Oral Pathology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, China
| | - Yuhan Wang
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, China
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, China
| | - Wanqiu Lu
- Central Laboratory, School of Biopharmacy, China Pharmaceutical University, Nanjing, 210023, Jiangsu, China
| | - Zijian Liu
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, China
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, China
| | - Yuxian Song
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, China
| | - Sheng Chen
- Department of Oral Pathology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, China
| | - Shu Xia
- Department of Oral Pathology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, China
| | - Huiling Li
- Department of Oral Pathology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, China
| | - Pei Weng
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, China
| | - Yue Jing
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, China
| | - Qiuya Yu
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, China
| | - Feng Zhu
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, China.
| | - Xiaoxin Zhang
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, China.
| | - Xiaofeng Huang
- Department of Oral Pathology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, China.
| | - Yanhong Ni
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, China.
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Kumar A, Vaiphei KK, Gulbake A. A nanotechnology driven effectual localized lung cancer targeting approaches using tyrosine kinases inhibitors: Recent progress, preclinical assessment, challenges, and future perspectives. Int J Pharm 2024; 666:124745. [PMID: 39321904 DOI: 10.1016/j.ijpharm.2024.124745] [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: 07/09/2024] [Revised: 09/09/2024] [Accepted: 09/21/2024] [Indexed: 09/27/2024]
Abstract
The higher incidence and mortality rate among all populations worldwide explains the unmet solutions in the treatment of lung cancer. The evolution of targeted therapies using tyrosine kinase inhibitors (TKI) has encouraged anticancer therapies. However, on-target and off-target effects and the development of drug resistance limited the anticancer potential of such targeted biologics. The advances in nanotechnology-driven-TKI embedded carriers that offered a new path toward lung cancer treatment. It is the inhalation route of administration known for its specific, precise, and efficient drug delivery to the lungs. The development of numerous TKI-nanocarriers through inhalation is proof of TKI growth. The future scopes involve using potential lung cancer biomarkers to achieve localized active cancer-targeting strategies. The adequate knowledge of in vitro absorption models usually helps establish better in vitro - in vivo correlation/extrapolation (IVIVC/E) to successfully evaluate inhalable drugs and drug products. The advanced in vitro and ex vivo lung tissue/ organ models offered better tumor heterogeneity, etiology, and microenvironment heterogeneity. The involvement of lung cancer organoids (LCOs), human organ chip models, and genetically modified mouse models (GEMMs) has resolved the challenges associated with conventional in vitro and in vivo models. To access potential inhalation-based drugtherapies, biological barriers, drug delivery, device-based challenges, and regulatory challenges must be encountered associated with their development. A proper understanding of material toxicity, size-based particle deposition at active disease sites, mucociliary clearance, phagocytosis, and the presence of enzymes and surfactants are required to achieve successful inhalational drug delivery (IDD). This article summarizes the future of lung cancer therapy using targeted drug-mediated inhalation using TKI.
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Affiliation(s)
- Ankaj Kumar
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research Guwahati, Assam 781101, India
| | - Klaudi K Vaiphei
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research Guwahati, Assam 781101, India
| | - Arvind Gulbake
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research Guwahati, Assam 781101, India.
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Nashaat Alnagar A, Motawea A, Elamin KM, Abu Hashim II. Hyaluronic acid/lactoferrin-coated polydatin/PLGA nanoparticles for active targeting of CD44 receptors in lung cancer. Pharm Dev Technol 2024; 29:1016-1032. [PMID: 39392049 DOI: 10.1080/10837450.2024.2414937] [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: 05/25/2024] [Revised: 10/06/2024] [Accepted: 10/07/2024] [Indexed: 10/12/2024]
Abstract
Traditional chemotherapeutic drugs lack optimal efficacy and invoke severe adverse effects in cancer patients. Polydatin (PD), a phytomedicine, has gradually gained attention due to its antitumor activity. However, its low solubility and poor bioavailability are still cornerstone issues. The present study aimed to fabricate and develop hyaluronic acid/lactoferrin-double coated PD/PLGA nanoparticles via a layer-by-layer self-assembly technique for active targeting of CD44 receptors in lung cancer. Different molecular weights (M.wt.) of HA (32 and 110 kDa) were exploited to study the relationship between the HA M.wt. and the NPs targeting efficacy. The optimized formulations were fully characterized. Their cytotoxicity and cellular uptake were investigated against A549 cell line by CCK-8 kit and fluorescence imaging, respectively. Finally, HA110/Lf-coated PD/PLGA NPs (F9) were subjected to a competitive inhibition study to prove internalization through CD44 overexpressed receptors. The results verified the fabrication of F9 with a particle size of 174.87 ± 3.97 nm and a zeta potential of -24.37 ± 1.19 mV as well as spherical NPs architecture. Importantly, it provoked enhanced cytotoxicity (IC50 = 0.57 ± 0.02 µg/mL) and superior cellular uptake efficacy. To conclude, the current investigation lays the foundation for the prospective therapeutic avenue of F9 for active targeting of CD44 receptors in lung cancer.
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Affiliation(s)
- Ahmed Nashaat Alnagar
- Department of Pharmaceutics, Faculty of Pharmacy, Mansoura University, Mansoura, Dakahlia, Egypt
| | - Amira Motawea
- Department of Pharmaceutics, Faculty of Pharmacy, Mansoura University, Mansoura, Dakahlia, Egypt
| | - Khaled M Elamin
- Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Irhan Ibrahim Abu Hashim
- Department of Pharmaceutics, Faculty of Pharmacy, Mansoura University, Mansoura, Dakahlia, Egypt
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Huang W, Guo Y, Qian Y, Liu X, Li G, Wang J, Yang X, Wu M, Fan Y, Luo H, Chen Y, Zhang L, Yang N, Liu Z, Liu Y. Ferroptosis-inducing compounds synergize with docetaxel to overcome chemoresistance in docetaxel-resistant non-small cell lung cancer cells. Eur J Med Chem 2024; 276:116670. [PMID: 39018922 DOI: 10.1016/j.ejmech.2024.116670] [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: 04/23/2024] [Revised: 07/02/2024] [Accepted: 07/09/2024] [Indexed: 07/19/2024]
Abstract
Development of resistance to therapy-induced cell death is a major hurdle in the effective treatment of advanced solid tumors. Erastin and RSL3 were originally found to induce synthetic lethality by induction of a novel form of cell death termed ferroptosis. Emerging evidence suggests that ferroptosis inducers enhance chemosensitivity of classic therapeutic agents by triggering ferroptotic cell death. In this study we evaluated the effects of erastin and RSL3 on the resistance of docetaxel, doxorubicin, and cisplatin, and revealed a mechanism whereby these ferroptosis inducers augment docetaxel efficacy in non-small cell lung cancer by regulating redox signaling to promote ferroptosis. Transcriptome analysis revealed that combination treatment modulated not only p53 signaling pathway but also immune responses and several signaling pathways including MAPK, NF-κB and PI3K/Akt. Considering that glutathione peroxidase 4 (GPX4) serves as the main effector to protect cells from ferroptosis, this study identified three novel non-covalent GPX4 inhibitors with the aid of pharmacophore-based virtual screening. The new ferroptosis-inducing compounds synergized with docetaxel to increase the cytotoxicity by promoting ferroptotic cell death in docetaxel-resistant A549/DTX cells. Collectively, the induction of ferroptosis contributed to docetaxel-induced cytotoxic effects and overcame drug resistance in A549/DTX cells. Ferroptosis has a great potential to become a new approach to attenuate resistance to some classic therapeutic drugs in cancer patients.
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Affiliation(s)
- Wei Huang
- Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, 100005, PR China.
| | - Yi Guo
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China
| | - Yazhi Qian
- Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, 100005, PR China
| | - Xiaoang Liu
- Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, 100005, PR China
| | - Gaoxiang Li
- Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, 100005, PR China; Medical College, Tibet University, Lhasa, Tibet Autonomous Region, 850000, PR China
| | - Jun Wang
- Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, 100005, PR China
| | - Xiaozhou Yang
- Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, 100005, PR China
| | - Mo Wu
- Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, 100005, PR China
| | - Ying Fan
- Medical College, Tibet University, Lhasa, Tibet Autonomous Region, 850000, PR China
| | - Haojun Luo
- Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, 100005, PR China
| | - Yuzhu Chen
- Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, 100005, PR China
| | - Liangren Zhang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China
| | - Nan Yang
- Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, 100005, PR China
| | - Zhenming Liu
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China.
| | - Yanyong Liu
- Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, 100005, PR China; Medical College, Tibet University, Lhasa, Tibet Autonomous Region, 850000, PR China.
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Paramanantham A, Asfiya R, Manjunath Y, Xu L, McCully G, Das S, Yang H, Kaifi JT, Srivastava A. Induction of Ferroptosis by an Amalgam of Extracellular Vesicles and Iron Oxide Nanoparticles Overcomes Cisplatin Resistance in Lung Cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.19.608664. [PMID: 39229071 PMCID: PMC11370464 DOI: 10.1101/2024.08.19.608664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/05/2024]
Abstract
Extracellular vesicles (EVs) hold potential as effective carriers for drug delivery, providing a promising approach to resolving challenges in lung cancer treatment. Traditional treatments, such as with the chemotherapy drug cisplatin, encounter resistance in standard cell death pathways like apoptosis, prompting the need to explore alternative approaches. This study investigates the potential of iron oxide nanoparticles (IONP) and EVs to induce ferroptosis-a regulated cell death mechanism-in lung cancer cells. We formulated a novel EV and IONP-based system, namely 'ExoFeR', and observed that ExoFeR demonstrated efficient ferroptosis induction, evidenced by downregulation of ferroptosis markers (xCT/SLC7A11 and GPX4), increased intracellular and mitochondrial ferrous iron levels, and morphological changes in mitochondria. To enhance efficacy, tumor-targeting transferrin (TF)-conjugated ExoFeR (ExoFeR TF ) was developed. ExoFeR TF outperformed ExoFeR, exhibiting higher uptake and cell death in lung cancer cells. Mechanistically, nuclear factor erythroid 2-related factor 2 (Nrf2)-a key regulator of genes involved in glutathione biosynthesis, antioxidant responses, lipid metabolism, and iron metabolism-was found downregulated in the ferroptotic cells. Inhibition of Nrf2 intracellular translocation in ExoFeR TF -treated cells was also observed, emphasizing the role of Nrf2 in modulating ferroptosis-dependent cell death. Furthermore, ExoFeR and ExoFeR TF demonstrated the ability to sensitize chemo-resistant cancer cells, including cisplatin-resistant lung cancer patient-derived tumoroid organoids. In summary, ExoFeR TF presents a promising and multifaceted therapeutic approach for combating lung cancer by intrinsically inducing ferroptosis and sensitizing chemo-resistant cells.
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Coradduzza D, Congiargiu A, Azara E, Mammani IMA, De Miglio MR, Zinellu A, Carru C, Medici S. Heavy metals in biological samples of cancer patients: a systematic literature review. Biometals 2024; 37:803-817. [PMID: 38347295 PMCID: PMC11254964 DOI: 10.1007/s10534-024-00583-4] [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: 03/24/2023] [Accepted: 01/07/2024] [Indexed: 07/18/2024]
Abstract
The majority of the so-called heavy metals are suspected to be involved in a number of pathologies and play a role in human carcinogenesis. Some of them (i.e. arsenic (As), cadmium (Cd), chromium (Cr), lead (Pb), mercury (Hg) and nickel (Ni)) have been defined as carcinogens, increasing the susceptibility of tumor development and progression in humans. Moreover, Ni, Cr, Cd, Hg, and Pb together with zinc (Zn) and iron (Fe), may be capable of stimulating the progression of breast cancer and reducing a patient's sensitivity to treatment through alterations to DNA methylation. In patients with gastric cancers, levels of various heavy metals are augmented and hypothesized to amplify the expression of the human epidermal growth factor receptor type 2 gene. Cd may increase the risk of lung cancer development and have a negative impact on the overall survival of lung cancer patients. To investigate the relation between heavy metals in biological samples and risk, occurrence and survival cancer individuals, a comprehensive review work was performed, with a focus on breast, lung, prostate and gastric cancers. An extensive search strategy was devised to ensure relevant literature could be identified, with the PECO framework being adopted to facilitate this and identify key search terms. As evidenced in this review, there is substantial data to support the hypothesis that heavy metals influence tumor development and progression. Unluckily the number of papers dealing with the determination of metals directly in samples from cancer tissues is still rather limited, so we decided to expand the scope of this review also to analyses carried out on other biological samples, as urine, plasma, hair, nail, etc. The studies reviewed showed that several limitations and current knowledge gaps are present in the literature that require further investigation to improve our comprehension of the impact of different heavy metals on tumorigenesis.
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Affiliation(s)
- Donatella Coradduzza
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/B, 07100, Sassari, Italy.
| | - Antonella Congiargiu
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/B, 07100, Sassari, Italy
| | - Emanuela Azara
- Institute of Biomolecular Chemistry, National Research Council, Sassari, Italy
| | | | - Maria Rosaria De Miglio
- Department of Medical, Surgery and Experimental Sciences, University of Sassari, Sassari, Italy
| | - Angelo Zinellu
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/B, 07100, Sassari, Italy
| | - Ciriaco Carru
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/B, 07100, Sassari, Italy.
| | - Serenella Medici
- Department of Chemistry and Pharmacy, University of Sassari, Vienna 2, 07100, Sassari, Italy
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11
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Li Y, Tuerxun H, Zhao Y, Liu X, Li X, Wen S, Zhao Y. The new era of lung cancer therapy: Combining immunotherapy with ferroptosis. Crit Rev Oncol Hematol 2024; 198:104359. [PMID: 38615871 DOI: 10.1016/j.critrevonc.2024.104359] [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: 10/29/2023] [Revised: 03/12/2024] [Accepted: 04/10/2024] [Indexed: 04/16/2024] Open
Abstract
Ferroptosis is an unconventional programmed cell death mode caused by phospholipid peroxidation dependent on iron. Emerging immunotherapies (especially immune checkpoint inhibitors) have the potential to enhance lung cancer patients' long-term survival. Although immunotherapy has yielded significant positive applications in some patients, there are still many mechanisms that can cause lung cancer cells to evade immunity, thus leading to the failure of targeted therapies. Immune-tolerant cancer cells are insensitive to conventional death pathways such as apoptosis and necrosis, whereas mesenchymal and metastasis-prone cancer cells are particularly vulnerable to ferroptosis, which plays a vital role in mediating immune tolerance resistance by tumors and immune cells. As a result, triggering lung cancer cell ferroptosis holds significant therapeutic potential for drug-resistant malignancies. Here, we summarize the mechanisms underlying the suppression of ferroptosis in lung cancer, highlight its function in the lung cancer immune microenvironment, and propose possible therapeutic strategies.
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Affiliation(s)
- Yawen Li
- Cancer Center, the First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Halahati Tuerxun
- Cancer Center, the First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Yixin Zhao
- Cancer Center, the First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Xingyu Liu
- Cancer Center, the First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Xi Li
- Cancer Center, the First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Shuhui Wen
- Cancer Center, the First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Yuguang Zhao
- Cancer Center, the First Hospital of Jilin University, Changchun, Jilin 130021, China.
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12
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Urbano-Gámez JD, Guzzi C, Bernal M, Solivera J, Martínez-Zubiaurre I, Caro C, García-Martín ML. Tumor versus Tumor Cell Targeting in Metal-Based Nanoparticles for Cancer Theranostics. Int J Mol Sci 2024; 25:5213. [PMID: 38791253 PMCID: PMC11121233 DOI: 10.3390/ijms25105213] [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: 04/11/2024] [Revised: 05/05/2024] [Accepted: 05/08/2024] [Indexed: 05/26/2024] Open
Abstract
The application of metal-based nanoparticles (mNPs) in cancer therapy and diagnostics (theranostics) has been a hot research topic since the early days of nanotechnology, becoming even more relevant in recent years. However, the clinical translation of this technology has been notably poor, with one of the main reasons being a lack of understanding of the disease and conceptual errors in the design of mNPs. Strikingly, throughout the reported studies to date on in vivo experiments, the concepts of "tumor targeting" and "tumor cell targeting" are often intertwined, particularly in the context of active targeting. These misconceptions may lead to design flaws, resulting in failed theranostic strategies. In the context of mNPs, tumor targeting can be described as the process by which mNPs reach the tumor mass (as a tissue), while tumor cell targeting refers to the specific interaction of mNPs with tumor cells once they have reached the tumor tissue. In this review, we conduct a critical analysis of key challenges that must be addressed for the successful targeting of either tumor tissue or cancer cells within the tumor tissue. Additionally, we explore essential features necessary for the smart design of theranostic mNPs, where 'smart design' refers to the process involving advanced consideration of the physicochemical features of the mNPs, targeting motifs, and physiological barriers that must be overcome for successful tumor targeting and/or tumor cell targeting.
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Affiliation(s)
- Jesús David Urbano-Gámez
- Biomedical Magnetic Resonance Laboratory—BMRL, Andalusian Public Foundation Progress and Health—FPS, 41092 Seville, Spain; (J.D.U.-G.); (C.G.)
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina–IBIMA Plataforma BIONAND, C/Severo Ochoa, 35, 29590 Malaga, Spain;
| | - Cinzia Guzzi
- Biomedical Magnetic Resonance Laboratory—BMRL, Andalusian Public Foundation Progress and Health—FPS, 41092 Seville, Spain; (J.D.U.-G.); (C.G.)
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina–IBIMA Plataforma BIONAND, C/Severo Ochoa, 35, 29590 Malaga, Spain;
| | - Manuel Bernal
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina–IBIMA Plataforma BIONAND, C/Severo Ochoa, 35, 29590 Malaga, Spain;
- Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, Universidad de Málaga, Andalucía Tech, 29071 Malaga, Spain
| | - Juan Solivera
- Department of Neurosurgery, Reina Sofia University Hospital, 14004 Cordoba, Spain;
| | - Iñigo Martínez-Zubiaurre
- Department of Clinical Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, P.O. Box 6050, Langnes, 9037 Tromsö, Norway;
| | - Carlos Caro
- Biomedical Magnetic Resonance Laboratory—BMRL, Andalusian Public Foundation Progress and Health—FPS, 41092 Seville, Spain; (J.D.U.-G.); (C.G.)
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina–IBIMA Plataforma BIONAND, C/Severo Ochoa, 35, 29590 Malaga, Spain;
| | - María Luisa García-Martín
- Biomedical Magnetic Resonance Laboratory—BMRL, Andalusian Public Foundation Progress and Health—FPS, 41092 Seville, Spain; (J.D.U.-G.); (C.G.)
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina–IBIMA Plataforma BIONAND, C/Severo Ochoa, 35, 29590 Malaga, Spain;
- Biomedical Research Networking Center in Bioengineering, Biomaterials & Nanomedicine (CIBER-BBN), 28029 Madrid, Spain
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13
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Hurrell BP, Sakano Y, Shen S, Helou DG, Li M, Shafiei-Jahani P, Kazemi MH, Sakano K, Li X, Quach C, Barbers R, Akbari O. Iron controls the development of airway hyperreactivity by regulating ILC2 metabolism and effector function. Sci Transl Med 2024; 16:eadk4728. [PMID: 38718131 DOI: 10.1126/scitranslmed.adk4728] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 04/09/2024] [Indexed: 11/06/2024]
Abstract
Group 2 innate lymphoid cells (ILC2s) rapidly induce a type 2 inflammation in the lungs in response to allergens. Here, we focused on the role of iron, a critical nutritional trace element, on ILC2 function and asthma pathogenesis. We found that transferrin receptor 1 (TfR1) is rapidly up-regulated and functional during ILC2 activation in the lungs, and blocking transferrin uptake reduces ILC2 expansion and activation. Iron deprivation reprogrammed ILC2 metabolism, inducing a HIF-1α-driven up-regulation of glycolysis and inhibition of oxidative mitochondrial activity. Consequently, we observed that in vivo iron chelation or induction of hypoferremia reduced the development of airway hyperreactivity in experimental models of ILC2-driven allergic asthma. Human circulating ILC2s rapidly induced TfR1 during activation, whereas inhibition of iron uptake or iron deprivation reduced effector functions. Last, we found a negative relationship between circulating ILC2 TfR1 expression and airway function in cohorts of patients with asthma. Collectively, our studies define cellular iron as a critical regulator of ILC2 function.
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Affiliation(s)
- Benjamin P Hurrell
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Yoshihiro Sakano
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Stephen Shen
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Doumet Georges Helou
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Meng Li
- USC Libraries Bioinformatics Service, University of Southern California, Los Angeles, CA 90033, USA
| | - Pedram Shafiei-Jahani
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Mohammad Hossein Kazemi
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Kei Sakano
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Xin Li
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Christine Quach
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Richard Barbers
- Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Omid Akbari
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
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14
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Yang NY, Zheng HH, Yu C, Ye Y, Xie GH. Diagnosis of Canine Tumours and the Value of Combined Detection of VEGF, P53, SF and NLRP3 for the Early Diagnosis of Canine Mammary Carcinoma. Animals (Basel) 2024; 14:1272. [PMID: 38731276 PMCID: PMC11083559 DOI: 10.3390/ani14091272] [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: 03/27/2024] [Revised: 04/21/2024] [Accepted: 04/21/2024] [Indexed: 05/13/2024] Open
Abstract
The average life of a dog is generally maintained at ten to fifteen years, and tumours are the predominant reason that leads to the death of dogs, especially canine mammary carcinoma. Therefore, early diagnosis of tumours is very important. In this study, tumor size, morphology, and texture could be seen through general clinical examination, tumor metastasis could be seen through imaging examination, inflammatory reactions could be seen through hematological examination, and abnormal cell morphology could be seen through cytological and histopathological examination. In the 269 malignant cases and 179 benign cases, we randomly selected 30 cases each, and an additional 30 healthy dogs were selected for the experiment (healthy dogs: dogs in good physical condition without any tumor or other diseases). We used RT-qPCR and ELISA to determine the relative expression of vascular endothelial growth factor (VEGF), tumor protein P53 (P53), serum ferritin (SF), and NOD-like receptor protein 3 (NLRP3) in 30 healthy dogs, 30 dogs with benign mammary tumours, and 30 dogs with malignant mammary tumours. In the results, the same expression trend was obtained both in serum and tissues, and the expression of the four markers was the highest in malignant mammary tumours, with highly significant differences compared with the benign and healthy/paracancerous groups. By plotting the ROC curves, it was found that the results of combined tests were better than a single test and the combination of the four markers was the best for the early diagnosis. In conclusion, this can assist the clinical early diagnosis to a certain extent, and also provides some references and assistance for the development of tumor detection kits in clinical practice.
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Affiliation(s)
- Ning-Yu Yang
- College of Veterinary Medicine, Jilin University, No. 5333 Xi’an Road, Changchun 130062, China; (N.-Y.Y.); (H.-H.Z.); (C.Y.); (Y.Y.)
| | - Hui-Hua Zheng
- College of Veterinary Medicine, Jilin University, No. 5333 Xi’an Road, Changchun 130062, China; (N.-Y.Y.); (H.-H.Z.); (C.Y.); (Y.Y.)
- College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Hangzhou 311300, China
| | - Chao Yu
- College of Veterinary Medicine, Jilin University, No. 5333 Xi’an Road, Changchun 130062, China; (N.-Y.Y.); (H.-H.Z.); (C.Y.); (Y.Y.)
| | - Yan Ye
- College of Veterinary Medicine, Jilin University, No. 5333 Xi’an Road, Changchun 130062, China; (N.-Y.Y.); (H.-H.Z.); (C.Y.); (Y.Y.)
| | - Guang-Hong Xie
- College of Veterinary Medicine, Jilin University, No. 5333 Xi’an Road, Changchun 130062, China; (N.-Y.Y.); (H.-H.Z.); (C.Y.); (Y.Y.)
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15
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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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16
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Liu S, Yao Y, Hou M, Mei J, Sun L, Zhang G. Identification and validation of a ferroptosis-related signature for prediction of the prognosis and tumor microenvironment in patients with chromophobe renal cell carcinoma. BMC Cancer 2023; 23:1079. [PMID: 37940859 PMCID: PMC10634106 DOI: 10.1186/s12885-023-11589-5] [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: 04/22/2023] [Accepted: 10/30/2023] [Indexed: 11/10/2023] Open
Abstract
BACKGROUND Ferroptosis is a novel form of regulated cell death that is different from other forms, which has an important role in tumor growth inhibition. The purpose of this study was to construct and validate a prognostic signature related to ferroptosis in chromophobe renal cell carcinoma (ChRCC) and to explore its role in immune cell infiltration and systemic therapy. METHODS The gene expression profiles of ChRCC patients obtained from The Cancer Genome Atlas (TCGA) database were used to identify differentially expressed prognostic ferroptosis-related genes (FRGs) by univariate Cox proportional hazards analyses. Ferroptosis molecular subtypes were obtained by consensus clustering analysis. The FRG-based signature in the training set was established by least absolute shrinkage and selection operator analysis and verified in the testing set. The association between molecular subtypes and the prognostic signature and immune microenvironment was explored to predict responses to immunotherapy. Immunohistochemistry was used to verify expression of the FRG-based signature externally. RESULTS ChRCC patients were divided into two FRG subtypes. Two FRGs (TFRC and SLC7A11) were identified to construct the prognostic signature. The high-risk group and cluster 2 had worse overall survival than the low-risk group and cluster 1, respectively. The low-risk group and cluster 1 had higher levels of immune cell infiltration and expression of MHC and immune checkpoint molecules than the high-risk group and cluster 2. The risk score was a predictor of overall survival and had a good predictive ability, which was verified in the testing set and evaluated by ROC and calibration curves. The high-risk group had a higher tumor mutation burden. The different sensitivities of targeted drugs in patients with different risks were evaluated. External immunohistochemical analysis showed that TFRC and SLC7A11 were highly expressed in tumor tissues compared with para-cancer normal tissues, and the expression level was significantly associated with a more advanced stage and worse cancer-specific survival. CONCLUSIONS An FRG signature was identified and validated to predict the clinicopathological features and prognosis of ChRCC. A significant association between the signature and immune cell infiltration, immune checkpoint expression, and drug response is helpful to guide comprehensive treatment of ChRCC.
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Affiliation(s)
- Shuai Liu
- Department of Urology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Rd, 266003, Qingdao, P.R. China
| | - Yu Yao
- Department of Urology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Rd, 266003, Qingdao, P.R. China
| | - Mingyu Hou
- Department of Pathology, The Affiliated Hospital of Qingdao University, 266003, Qingdao, P.R. China
| | - Jingchang Mei
- Department of Urology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Rd, 266003, Qingdao, P.R. China
| | - Lijiang Sun
- Department of Urology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Rd, 266003, Qingdao, P.R. China
| | - Guiming Zhang
- Department of Urology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Rd, 266003, Qingdao, P.R. China.
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17
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Hinokuma H, Kanamori Y, Ikeda K, Hao L, Maruno M, Yamane T, Maeda A, Nita A, Shimoda M, Niimura M, Takeshima Y, Li S, Suzuki M, Moroishi T. Distinct functions between ferrous and ferric iron in lung cancer cell growth. Cancer Sci 2023; 114:4355-4364. [PMID: 37688294 PMCID: PMC10637068 DOI: 10.1111/cas.15949] [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: 05/10/2023] [Revised: 08/19/2023] [Accepted: 08/21/2023] [Indexed: 09/10/2023] Open
Abstract
Accumulating evidence suggests an association between iron metabolism and lung cancer progression. In biological systems, iron is present in either reduced (Fe2+ ; ferrous) or oxidized (Fe3+ ; ferric) states. However, ferrous and ferric iron exhibit distinct chemical and biological properties, the role of ferrous and ferric iron in lung cancer cell growth has not been clearly distinguished. In this study, we manipulated the balance between cellular ferrous and ferric iron status by inducing gene mutations involving the FBXL5-IRP2 axis, a ubiquitin-dependent regulatory system for cellular iron homeostasis, and determined its effects on lung cancer cell growth. FBXL5 depletion (ferrous iron accumulation) was found to suppress lung cancer cell growth, whereas IRP2 depletion (ferric iron accumulation) did not suppress such growth, suggesting that ferrous iron but not ferric iron plays a suppressive role in cell growth. Mechanistically, the depletion of FBXL5 impaired the degradation of the cyclin-dependent kinase inhibitor, p27, resulting in a delay in the cell cycle at the G1/S phase. FBXL5 depletion in lung cancer cells also improved the survival of tumor-bearing mice. Overall, this study highlights the important function of ferrous iron in cell cycle progression and lung cancer cell growth.
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Affiliation(s)
- Hironori Hinokuma
- Department of Molecular and Medical Pharmacology, Faculty of Life SciencesKumamoto UniversityKumamotoJapan
- Department of Thoracic and Breast Surgery, Graduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Yohei Kanamori
- Department of Molecular and Medical Pharmacology, Faculty of Life SciencesKumamoto UniversityKumamotoJapan
| | - Koei Ikeda
- Department of Thoracic and Breast Surgery, Graduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Li Hao
- Department of Molecular and Medical Pharmacology, Faculty of Life SciencesKumamoto UniversityKumamotoJapan
| | - Masataka Maruno
- Department of Molecular and Medical Pharmacology, Faculty of Life SciencesKumamoto UniversityKumamotoJapan
| | - Taishi Yamane
- Department of Molecular and Medical Pharmacology, Faculty of Life SciencesKumamoto UniversityKumamotoJapan
| | - Ayato Maeda
- Department of Molecular and Medical Pharmacology, Faculty of Life SciencesKumamoto UniversityKumamotoJapan
| | - Akihiro Nita
- Department of Molecular and Medical Pharmacology, Faculty of Life SciencesKumamoto UniversityKumamotoJapan
| | - Mayuko Shimoda
- Department of Molecular and Medical Pharmacology, Faculty of Life SciencesKumamoto UniversityKumamotoJapan
| | - Mayumi Niimura
- Department of Molecular and Medical Pharmacology, Faculty of Life SciencesKumamoto UniversityKumamotoJapan
| | - Yuki Takeshima
- Department of Molecular and Medical Pharmacology, Faculty of Life SciencesKumamoto UniversityKumamotoJapan
| | - Shuran Li
- Department of Molecular and Medical Pharmacology, Faculty of Life SciencesKumamoto UniversityKumamotoJapan
| | - Makoto Suzuki
- Department of Thoracic and Breast Surgery, Graduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Toshiro Moroishi
- Department of Molecular and Medical Pharmacology, Faculty of Life SciencesKumamoto UniversityKumamotoJapan
- Center for Metabolic Regulation of Healthy Aging, Faculty of Life SciencesKumamoto UniversityKumamotoJapan
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18
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Robinson TP, Hamidi T, Counts B, Guttridge DC, Ostrowski MC, Zimmers TA, Koniaris LG. The impact of inflammation and acute phase activation in cancer cachexia. Front Immunol 2023; 14:1207746. [PMID: 38022578 PMCID: PMC10644737 DOI: 10.3389/fimmu.2023.1207746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 10/13/2023] [Indexed: 12/01/2023] Open
Abstract
The development of cachexia in the setting of cancer or other chronic diseases is a significant detriment for patients. Cachexia is associated with a decreased ability to tolerate therapies, reduction in ambulation, reduced quality of life, and increased mortality. Cachexia appears intricately linked to the activation of the acute phase response and is a drain on metabolic resources. Work has begun to focus on the important inflammatory factors associated with the acute phase response and their role in the immune activation of cachexia. Furthermore, data supporting the liver, lung, skeletal muscle, and tumor as all playing a role in activation of the acute phase are emerging. Although the acute phase is increasingly being recognized as being involved in cachexia, work in understanding underlying mechanisms of cachexia associated with the acute phase response remains an active area of investigation and still lack a holistic understanding and a clear causal link. Studies to date are largely correlative in nature, nonetheless suggesting the possibility for a role for various acute phase reactants. Herein, we examine the current literature regarding the acute phase response proteins, the evidence these proteins play in the promotion and exacerbation of cachexia, and current evidence of a therapeutic potential for patients.
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Affiliation(s)
- Tyler P. Robinson
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Tewfik Hamidi
- Department of Surgery, Oregon Health Sciences University, Portland, OR, United States
| | - Brittany Counts
- Department of Surgery, Oregon Health Sciences University, Portland, OR, United States
| | - Denis C. Guttridge
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States
| | - Michael C. Ostrowski
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States
| | - Teresa A. Zimmers
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
- Department of Surgery, Oregon Health Sciences University, Portland, OR, United States
| | - Leonidas G. Koniaris
- Department of Surgery, Oregon Health Sciences University, Portland, OR, United States
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Chinnappan R, Mir TA, Alsalameh S, Makhzoum T, Alzhrani A, Alnajjar K, Adeeb S, Al Eman N, Ahmed Z, Shakir I, Al-Kattan K, Yaqinuddin A. Emerging Biosensing Methods to Monitor Lung Cancer Biomarkers in Biological Samples: A Comprehensive Review. Cancers (Basel) 2023; 15:3414. [PMID: 37444523 DOI: 10.3390/cancers15133414] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Revised: 06/21/2023] [Accepted: 06/22/2023] [Indexed: 07/15/2023] Open
Abstract
Lung cancer is the most commonly diagnosed of all cancers and one of the leading causes of cancer deaths among men and women worldwide, causing 1.5 million deaths every year. Despite developments in cancer treatment technologies and new pharmaceutical products, high mortality and morbidity remain major challenges for researchers. More than 75% of lung cancer patients are diagnosed in advanced stages, leading to poor prognosis. Lung cancer is a multistep process associated with genetic and epigenetic abnormalities. Rapid, accurate, precise, and reliable detection of lung cancer biomarkers in biological fluids is essential for risk assessment for a given individual and mortality reduction. Traditional diagnostic tools are not sensitive enough to detect and diagnose lung cancer in the early stages. Therefore, the development of novel bioanalytical methods for early-stage screening and diagnosis is extremely important. Recently, biosensors have gained tremendous attention as an alternative to conventional methods because of their robustness, high sensitivity, inexpensiveness, and easy handling and deployment in point-of-care testing. This review provides an overview of the conventional methods currently used for lung cancer screening, classification, diagnosis, and prognosis, providing updates on research and developments in biosensor technology for the detection of lung cancer biomarkers in biological samples. Finally, it comments on recent advances and potential future challenges in the field of biosensors in the context of lung cancer diagnosis and point-of-care applications.
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Affiliation(s)
- Raja Chinnappan
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
- Laboratory of Tissue/Organ Bioengineering & BioMEMS, Organ Transplant Centre of Excellence, Transplant Research & Innovation Department, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Tanveer Ahmad Mir
- Laboratory of Tissue/Organ Bioengineering & BioMEMS, Organ Transplant Centre of Excellence, Transplant Research & Innovation Department, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | | | - Tariq Makhzoum
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Alaa Alzhrani
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
- Laboratory of Tissue/Organ Bioengineering & BioMEMS, Organ Transplant Centre of Excellence, Transplant Research & Innovation Department, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
- Medical Laboratory Technology Department, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Khalid Alnajjar
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Salma Adeeb
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Noor Al Eman
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Zara Ahmed
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Ismail Shakir
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Khaled Al-Kattan
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Ahmed Yaqinuddin
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
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Petronek MS, Bayanbold K, Amegble K, Tomanek-Chalkley AM, Allen BG, Spitz DR, Bailey CK. Evaluating the iron chelator function of sirtinol in non-small cell lung cancer. Front Oncol 2023; 13:1185715. [PMID: 37397370 PMCID: PMC10313412 DOI: 10.3389/fonc.2023.1185715] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Accepted: 05/25/2023] [Indexed: 07/04/2023] Open
Abstract
A distinctive feature of cancer is the upregulation of sirtuin proteins. Sirtuins are class III NAD+-dependent deacetylases involved in cellular processes such as proliferation and protection against oxidative stress. SIRTs 1 and 2 are also overexpressed in several types of cancers including non-small cell lung cancer (NSCLC). Sirtinol, a sirtuin (SIRT) 1 and 2 specific inhibitor, is a recent anti-cancer agent that is cytotoxic against several types of cancers including NSCLC. Thus, sirtuins 1 and 2 represent valuable targets for cancer therapy. Recent studies show that sirtinol functions as a tridentate iron chelator by binding Fe3+ with 3:1 stoichiometry. However, the biological consequences of this function remain unexplored. Consistent with preliminary literature, we show that sirtinol can deplete intracellular labile iron pools in both A549 and H1299 non-small cell lung cancer cells acutely. Interestingly, a temporal adaptive response occurs in A549 cells as sirtinol enhances transferrin receptor stability and represses ferritin heavy chain translation through impaired aconitase activity and apparent IRP1 activation. This effect was not observed in H1299 cells. Holo-transferrin supplementation significantly enhanced colony formation in A549 cells while increasing sirtinol toxicity. This effect was not observed in H1299 cells. The results highlight the fundamental genetic differences that may exist between H1299 and A549 cells and offer a novel mechanism of how sirtinol kills NSCLC cells.
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Affiliation(s)
- Michael S. Petronek
- Department of Radiation Oncology, Division of Free Radical and Radiation Biology, University of Iowa, Iowa City, IA, United States
| | - Khaliunaa Bayanbold
- Department of Radiation Oncology, Division of Free Radical and Radiation Biology, University of Iowa, Iowa City, IA, United States
| | - Koffi Amegble
- Department of Biology, Grinnell College, Grinnell, IA, United States
| | - Ann M. Tomanek-Chalkley
- Department of Radiation Oncology, Division of Free Radical and Radiation Biology, University of Iowa, Iowa City, IA, United States
| | - Bryan G. Allen
- Department of Radiation Oncology, Division of Free Radical and Radiation Biology, University of Iowa, Iowa City, IA, United States
| | - Douglas R. Spitz
- Department of Radiation Oncology, Division of Free Radical and Radiation Biology, University of Iowa, Iowa City, IA, United States
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21
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Wu X, Jiao Z, Zhang J, Li F, Li Y. Expression of TFRC helps to improve the antineoplastic effect of Ara-C on AML cells through a targeted delivery carrier. J Nanobiotechnology 2023; 21:126. [PMID: 37041636 PMCID: PMC10088114 DOI: 10.1186/s12951-023-01881-8] [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: 01/09/2023] [Accepted: 04/06/2023] [Indexed: 04/13/2023] Open
Abstract
BACKGROUND Currently, high doses of cytarabine arabinoside (Ara-C)-based combined chemotherapy are commonly used in acute myeloid leukemia (AML) therapy, but severe adverse effects and poor suppression effects in leukemia cells limit the clinical therapeutic efficiency of Ara-C-based chemotherapy due to a lack of targeting selectivity. To improve the therapeutic effect of Ara-C in AML, here, since we confirmed that transferrin receptor 1 (TFRC) expression in AML cells was constant, we generated Ara-C@HFn by encapsulating free Ara-C into self-assembled heavy ferritin chain (HFn, the ligand of TFRC) nanocages. RESULTS The analysis of clinically relevant data suggested that the high expression levels of TFRC from AML cells would not decrease significantly after treatment with Ara-C. Ara-C@HFn can be efficiently internalized by leukemia cells, showing stronger cytotoxic effects in vitro and reducing the burden of leukemia in AML mice more effectively in vivo than free Ara-C. Ara-C@HFn treatment showed no acute toxicity in visceral organs of mice. Moreover, the analysis of clinically relevant data also suggested that there are several drugs (such as tamibarotene and ABT199) that would not cause significant expression down-regulation of TFRC in AML cells (after treatment). CONCLUSION The above results suggested that TFRC can be used as a constant and effective target for drug targeting delivery of AML cells. Thus Ara-C@HFn treatment can become a safe and efficient strategy for AML therapy by specifically delivering Ara-C to AML cells. Besides, the HFn nanocages are promising for improving antineoplastic effect of other AML-related therapy drugs that do not cause downregulated expression of TFRC in AML cells.
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Affiliation(s)
- Xinzhou Wu
- Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, People's Republic of China
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, People's Republic of China
| | - Zhouguang Jiao
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, People's Republic of China.
| | - Junying Zhang
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, People's Republic of China
| | - Feng Li
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, People's Republic of China
| | - Yuhua Li
- Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, People's Republic of China.
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22
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Li P, Wu X, Chen P, Gu Z. Prognostic Significance of Iron Metabolism Related Genes in Human Lung Adenocarcinoma. Cancer Manag Res 2023; 15:203-216. [PMID: 36860893 PMCID: PMC9968870 DOI: 10.2147/cmar.s398982] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 01/25/2023] [Indexed: 02/24/2023] Open
Abstract
Background Iron metabolism related genes participate in cell proliferation, cell growth, and redox cycling in multiple cancers. Limited studies have revealed the roles and clinical significance of iron metabolism in the pathogenesis and prognosis of lung cancer. Methods A total of 119 iron metabolism related genes were extracted from MSigDB database and their prognostic values were determined in The Cancer Genome Atlas lung adenocarcinoma (TCGA-LUAD) dataset and the Gene Expression Profiling Interactive Analysis 2 (GEPIA 2) database. Immunohistochemistry technique and correlations with immune cell infiltration, gene mutation and drug resistance were used to identify the potential and underlying mechanisms of STEAP1 and STEAP2 as prognostic biomarkers of LUAD. Results The expression of STEAP1 and STEAP2 are negatively associated with the prognosis of LUAD patients both at the mRNA and protein level. The expression of STEAP1 and STEAP2 was not only negatively correlated with the trafficking degree of CD4+ T immune cells and positively related to most immune cells' trafficking degree, but also significantly associated with gene mutation status, particularly with mutations on TP53 and STK11. Four types of drug resistance showed significant correlation with the expression level of STEAP1 while 13 types of drug resistance were associated with the expression level of STEAP2. Conclusion Multiple iron metabolism related genes including STEAP1 and STEAP2 are significantly associated with the prognosis of LUAD patients. STEAP1 and STEAP2 might affect the prognosis of LUAD patients partially through immune cell infiltration, gene mutation and drug resistance, which indicated they were independent prognostic factors for LUAD patients.
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Affiliation(s)
- Pu Li
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
| | - Xiaoqiong Wu
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
| | - Peizhan Chen
- Clinical Research Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201821, People’s Republic of China,Peizhan Chen, Clinical Research Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201821, People’s Republic of China, Tel +86 13918550745, Email
| | - Zhidong Gu
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China,Department of Laboratory Medicine, Ruijin-Hainan Hospital, Shanghai Jiao Tong University School of Medicine (Hainan Boao Research Hospital), Hainan, People’s Republic of China,Correspondence: Zhidong Gu, Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201821, People’s Republic of China, Tel +86 13801653534, Email
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23
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Cai S, Ding Z, Liu X, Zeng J. Trabectedin induces ferroptosis via regulation of HIF-1α/IRP1/TFR1 and Keap1/Nrf2/GPX4 axis in non-small cell lung cancer cells. Chem Biol Interact 2023; 369:110262. [PMID: 36396105 DOI: 10.1016/j.cbi.2022.110262] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 10/24/2022] [Accepted: 11/10/2022] [Indexed: 11/16/2022]
Abstract
BACKGROUND AND OBJECTIVES Non-small cell lung cancer (NSCLC) is a global health concern. NSCLC treatment outcomes are generally poor due to treatment resistance or toxicity. Ferroptosis is a novel cell death triggered by iron accumulation, reactive oxygen species (ROS), and lipid peroxidation. Ferroptosis may kill cancer cells, particularly those resistant to apoptosis. MATERIALS AND METHODS The Cell Counting Kit-8 assay assessed NSCLC cell viability after trabectedin treatment. Flow cytometry with Annexin V-FITC staining evaluated cell death. ROS, iron, lipid peroxidation, and GSH levels were measured using commercial kits. qRT-PCR and western blots evaluated messenger RNA and protein levels. Proteins were inhibited using short interfering RNA transfection and specific inhibitors. RESULTS Trabectedin was cytotoxic to NSCLC cells regardless of p53 status. Trabectedin upregulated iron, ROS, and lipid peroxidation in NSCLC cells, causing ferroptosis. Trabectedin increases iron and ROS levels by upregulating transferrin receptor 1 and the HIF-1/IRP1 axis. In NSCLC cells, trabectedin suppresses glutathione peroxidase 4, followed by the Keap1/Nrf2 axis. CONCLUSIONS Our findings imply that trabectedin may treat NSCLC effectively.
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Affiliation(s)
- Shunv Cai
- Department of Anesthesiology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, People's Republic of China
| | - Zewu Ding
- Department of Anesthesiology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, People's Republic of China
| | - Xinyi Liu
- Department of Anesthesiology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, People's Republic of China
| | - Jian Zeng
- Department of Thoracic Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital). Zhejiang Key Laboratory of Diagnosis and Treatment Technology on Thoracic Oncology (Lung and Esophagus), The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, People's Republic of China.
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24
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Gao Y, Ge JT. Prognostic role of pretreatment serum ferritin concentration in lung cancer patients: A meta-analysis. World J Clin Cases 2022; 10:12230-12239. [PMID: 36483825 PMCID: PMC9724546 DOI: 10.12998/wjcc.v10.i33.12230] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 10/19/2022] [Accepted: 10/24/2022] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND The association between pretreatment serum ferritin concentration (SFC) and long-term survival in lung cancer remains unclear now. AIM To identify the prognostic value of pretreatment SFC in lung cancer patients based on current evidence. METHODS The PubMed, EMBASE and Web of Science databases were searched from inception to May 29, 2022 for relevant studies. The primary endpoint was overall survival (OS) and the hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) were combined to assess the predictive role of pretreatment SFC for long-term survival of lung cancer patients. The data were then extracted and assessed on the basis of the Reference Citation Analysis (https://www.referencecitationanalysis.com/). RESULTS Twelve retrospective studies involving 1654 patients were analyzed. The results manifested that increased pretreatment SFC was associated with worse OS (HR = 1.09, 95%CI: 1.03-1.15, P = 0.004). Subgroup analysis stratified by the country (China vs non-China) showed similar results. However, subgroup analysis stratified by tumor type revealed inconsistent results (lung cancer: HR = 1.39, P = 0.008; small cell lung cancer: HR = 1.99, P = 0.175; non-small cell lung cancer: HR = 1.03, P = 0.281). CONCLUSION Pretreatment SFC might serve as a promising prognostic indicator in lung cancer patients and elevated pretreatment SFC predicts worse prognosis. However, more high-quality studies with big sample sizes are still needed to further verify its prognostic value in lung cancer.
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Affiliation(s)
- Yang Gao
- Department of Cardiology Surgery, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Huaian 223001, Jiangsu Province, China
| | - Jin-Tong Ge
- Department of Cardiology Surgery, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Huaian 223001, Jiangsu Province, China
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25
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Li L, Gao Q, Wang J, Gu L, Li Z, Zhang S, Hu C, He M, Wang Y, Wang Z, Yi Y, Fu J, Zhang X, Ge F, Chen M, Zhang X. Induction of Ferroptosis by Ophiopogonin-B Through Regulating the Gene Signature AURKA in NSCLC. Front Oncol 2022; 12:833814. [PMID: 35875069 PMCID: PMC9299951 DOI: 10.3389/fonc.2022.833814] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 05/23/2022] [Indexed: 11/13/2022] Open
Abstract
Ferroptosis is a new type of iron-dependent programmed cell death. In recent years, its role in the diagnosis and treatment of multiple tumors, including non-small cell lung cancer (NSCLC), has been continuously observed. The relationship between the ferroptosis-related genes and the prognosis of patients with NSCLC needs to be clarified. In this study, The Cancer Genome Atlas (TCGA) and the Gene Expression Synthesis database (Gene Expression Omnibus, GEO) were used to build a model of ferroptosis-related differentially expressed genes (DEGs). A total of 101 ferroptosis-related DEGs were screened using R language, and a 12-gene signature was finally established through univariate Cox regression analysis and least absolute shrinkage and selection operator (LASSO)-penalized Cox regression analysis. According to the risk scores, the patients were divided into a high-risk or a low-risk group, with patients in the low-risk group showing better prognosis. AURKA, one of the genes in the 12-gene signature, was found to be highly expressed in tumors. In addition, further study verified AURKA to be a negative regulator of ferroptosis in NSCLC cells. Ophiopogonin B (OP-B) had been reported to induce apoptosis, mitotic catastrophe, and autophagy in NSCLC cells. Herein, proteomic sequencing analysis and OP-B administration revealed the upregulation of AURKA and the downregulation of PHKG2 and SLC7A5 in the 12-gene signature, indicating that OP-B induced ferroptosis in NSCLC. Determination of the concentrations of malondialdehyde (MDA), glutathione (GSH), and intracellular iron and the mitochondrial membrane potential (MMP) confirmed the induction of ferroptosis by OP-B in vitro. Furthermore, transmission electron microscopy (TEM) examination of lung cancer xenotransplantation in nude mice confirmed that OP-B induced ferroptosis in vivo. Further study of the molecular mechanism showed that the ferroptosis effect caused by OP-B can be partially reversed by the overexpression of AURKA. Overall, our study established a new ferroptosis-related risk prediction model for the prognosis of patients with NSCLC, revealed the enrichment pathways of ferroptosis in NSCLC, and discovered the negative regulation of AURKA in ferroptosis. On this basis, we demonstrated that OP-B can induce ferroptosis in NSCLC and clarified the specific molecular mechanism of OP-B inducing ferroptosis by regulating the expression of AURKA.
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Affiliation(s)
- Liqiu Li
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, China
| | - Qian Gao
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jin Wang
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Ling Gu
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- College of Traditional Chinese Medicine & Integrated Chinese and Western Medicine College, Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhihui Li
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Shiping Zhang
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Cheng Hu
- The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China
| | - Menglin He
- The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yulin Wang
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Zixuan Wang
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yongxiang Yi
- The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jin Fu
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xiongfei Zhang
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Fei Ge
- Department of Gastroenterology, Haian Hospital of Traditional Chinese Medicine, Nantong, China
- *Correspondence: Fei Ge, ; Meijuan Chen, ; Xu Zhang,
| | - Meijuan Chen
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- *Correspondence: Fei Ge, ; Meijuan Chen, ; Xu Zhang,
| | - Xu Zhang
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- *Correspondence: Fei Ge, ; Meijuan Chen, ; Xu Zhang,
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Mojarad-Jabali S, Mahdinloo S, Farshbaf M, Sarfraz M, Fatahi Y, Atyabi F, Valizadeh H. Transferrin receptor-mediated liposomal drug delivery: recent trends in targeted therapy of cancer. Expert Opin Drug Deliv 2022; 19:685-705. [PMID: 35698794 DOI: 10.1080/17425247.2022.2083106] [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] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Compared to normal cells, malignant cancer cells require more iron for their growth and rapid proliferation, which can be supplied by a high expression level of transferrin receptor (TfR). It is well known that the expression of TfR on the tumor cells is considerably higher than that of normal cells, which makes TfR an attractive target in cancer therapy. AREAS COVERED In this review, the primary focus is on the role of TfR as a valuable tool for cancer-targeted drug delivery, followed by the full coverage of available TfR ligands and their conjugation chemistry to the surface of liposomes. Finally, the most recent studies investigating the potential of TfR-targeted liposomes as promising drug delivery vehicles to different cancer cells are highlighted with emphasis on their improvement possibilities to become a part of future cancer medicines. EXPERT OPINION Liposomes as a valuable class of nanocarriers have gained much attention toward cancer therapy. From all the studies that have exploited the therapeutic and diagnostic potential of TfR on cancer cells, it can be realized that the systematic assessment of TfR ligands applied for liposomal targeted delivery has yet to be entirely accomplished.
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Affiliation(s)
- Solmaz Mojarad-Jabali
- Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.,Student research committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Somayeh Mahdinloo
- Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.,Student research committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Masoud Farshbaf
- Student research committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Muhammad Sarfraz
- College of Pharmacy, Al Ain University, Al Ain, United Arab Emirates
| | - Yousef Fatahi
- Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Atyabi
- Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Hadi Valizadeh
- Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.,Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Changes in target ability of nanoparticles due to protein corona composition and disease state. Asian J Pharm Sci 2022; 17:401-411. [PMID: 35782324 PMCID: PMC9237596 DOI: 10.1016/j.ajps.2022.03.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 01/14/2022] [Accepted: 03/04/2022] [Indexed: 01/10/2023] Open
Abstract
Many studies have shown the influence of protein corona (PC) on the active targeting capability of ligand-modified nanoparticles; however, the influence of clinical status on PC composition and targeting capacity is rarely discussed. In this study, when transferrin-modified PEGylated polystyrene nanoparticles (Tf-PNs) is intravenously injected into mice with non-small cell lung cancer (NSCLC) comorbid with type 2 diabetes mellitus (T2DM), more Tf-PNs accumulated in the tumor tissue than in those of NSCLC model mice. This indicated that PC derived from different states of disease changed the active targeting ability of Tf-PNs. To explain the occurrence of this phenomenon, our analysis of PC from different disease states revealed that Tf (transferrin) modification had no significant effect on the formation of PC, and that the PC from the NSCLC comorbid with T2DM model contained more proteins like fibrin and clusterin. This work demonstrates the impacts of comorbidity, such as with T2DM, on the active targeting capability of ligand-modified nanoparticles, and the results promote the application of nanoparticles for precision medicine.
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Ceci C, Lacal PM, Graziani G. Antibody-drug conjugates: Resurgent anticancer agents with multi-targeted therapeutic potential. Pharmacol Ther 2022; 236:108106. [PMID: 34990642 DOI: 10.1016/j.pharmthera.2021.108106] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 12/23/2021] [Accepted: 12/29/2021] [Indexed: 12/18/2022]
Abstract
Antibody-drug conjugates (ADCs) constitute a relatively new group of anticancer agents, whose first appearance took place about two decades ago, but a renewed interest occurred in recent years, following the success of anti-cancer immunotherapy with monoclonal antibodies. Indeed, an ADC combines the selectivity of a monoclonal antibody with the cell killing properties of a chemotherapeutic agent (payload), joined together through an appropriate linker. The antibody moiety targets a specific cell surface antigen expressed by tumor cells and/or cells of the tumor microenvironment and acts as a carrier that delivers the cytotoxic payload within the tumor mass. Despite advantages in terms of selectivity and potency, the development of ADCs is not devoid of challenges, due to: i) low tumor selectivity when the target antigens are not exclusively expressed by cancer cells; ii) premature release of the cytotoxic drug into the bloodstream as a consequence of linker instability; iii) development of tumor resistance mechanisms to the payload. All these factors may result in lack of efficacy and/or in no safety improvement compared to unconjugated cytotoxic agents. Nevertheless, the development of antibodies engineered to remain inert until activated in the tumor (e.g., antibodies activated proteolytically after internalization or by the acidic conditions of the tumor microenvironment) together with the discovery of innovative targets and cytotoxic or immunomodulatory payloads, have allowed the design of next-generation ADCs that are expected to possess improved therapeutic properties. This review provides an overview of approved ADCs, with related advantages and limitations, and of novel targets exploited by ADCs that are presently under clinical investigation.
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Affiliation(s)
- Claudia Ceci
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
| | | | - Grazia Graziani
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; IDI-IRCCS, Via Monti di Creta 104, 00167 Rome, Italy.
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Mahroum N, Alghory A, Kiyak Z, Alwani A, Seida R, Alrais M, Shoenfeld Y. Ferritin - from iron, through inflammation and autoimmunity, to COVID-19. J Autoimmun 2022; 126:102778. [PMID: 34883281 PMCID: PMC8647584 DOI: 10.1016/j.jaut.2021.102778] [Citation(s) in RCA: 94] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 12/03/2021] [Accepted: 12/03/2021] [Indexed: 01/08/2023]
Abstract
While it took decades to arrive to a conclusion that ferritin is more than an indicator of iron storage level, it took a short period of time through the COVID-19 pandemic to wonder what the reason behind high levels of ferritin in patients with severe COVID-19 might be. Unsurprisingly, acute phase reactant was not a satisfactory explanation. Moreover, the behavior of ferritin in patients with severe COVID-19 and the subsequent high mortality rates in patients with high ferritin levels necessitated further investigations to understand the role of ferritin in the diseases. Ferritin was initially described to accompany various acute infections, both viral and bacterial, indicating an acute response to inflammation. However, with the introduction of the hyperferritinemic syndrome connecting four severe pathological conditions such as adult-onset Still's disease, macrophage activation syndrome, catastrophic antiphospholipid syndrome, and septic shock added another aspect of ferritin where it could have a pathogenetic role rather than an extremely elevated protein only. In fact, suggesting that COVID-19 is a new member in the spectrum of hyperferritinemic syndrome besides the four mentioned conditions could hopefully direct further search on the pathogenetic role of ferritin. Doubtlessly, improving our understanding of those aspects of ferritin would enormously contribute to better coping with severe diseases in terms of treatment and prevention of complications. The origin, history, importance, and the advances of searching the role of ferritin in various pathological and clinical processes are presented hereby in our article. In addition, the implications of ferritin in COVID-19 are addressed.
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Affiliation(s)
- Naim Mahroum
- International School of Medicine, Istanbul Medipol University, Istanbul, Turkey,Internal Medicine B and Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Ramat- Gan, Israel,Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel,Corresponding author. Internal medicine “B” department, Sheba Medical Center (Affiliated to Tel-Aviv University), Tel-Hashomer, 5265601, Israel
| | - Amal Alghory
- International School of Medicine, Istanbul Medipol University, Istanbul, Turkey
| | - Zeynep Kiyak
- International School of Medicine, Istanbul Medipol University, Istanbul, Turkey
| | - Abdulkarim Alwani
- International School of Medicine, Istanbul Medipol University, Istanbul, Turkey
| | - Ravend Seida
- International School of Medicine, Istanbul Medipol University, Istanbul, Turkey
| | - Mahmoud Alrais
- International School of Medicine, Istanbul Medipol University, Istanbul, Turkey
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Park JM, Mau CZ, Chen YC, Su YH, Chen HA, Huang SY, Chang JS, Chiu CF. A case-control study in Taiwanese cohort and meta-analysis of serum ferritin in pancreatic cancer. Sci Rep 2021; 11:21242. [PMID: 34711879 PMCID: PMC8553768 DOI: 10.1038/s41598-021-00650-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 10/06/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is one of the most lethal diseases which lack an early diagnostic marker. We investigated whether serum ferritin (SF) reflects risk for pancreatic cancer and potential genes that may contribute ferritin and pancreatic cancer risks. We performed a meta-analysis of relevant studies on SF and pancreatic cancer risk by searching articles in PUBMED and EMBASE published up to 1 March 2020. We also collected serum samples from Taipei Medical University Joint Biobank and compared SF levels in 34 healthy controls and 34 pancreatic cancer patients. An Oncomine database was applied as a platform to explore a series of genes that exhibited strong associations between ferritin and pancreatic cancer. Herein, we show that high levels of SF can indicate risk of pancreatic cancer, suggesting SF as the new tumor marker that may be used to help pancreatic cancer diagnosis. We also found that expressions of iron homeostasis genes (MYC, FXN) and ferroptosis genes (ALOX15, CBS, FDFT1, LPCAT3, RPL8, TP53, TTC35) are significantly altered with pancreatic tumor grades, which may contribute to differential expression of ferritin related to pancreatic cancer prognosis.
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Affiliation(s)
- Ji Min Park
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei, 11031, Taiwan.,Graduate Institute of Metabolism and Obesity Sciences, College of Nutrition, Taipei Medical University, Taipei, 11031, Taiwan.,TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, 11031, Taiwan
| | - Chen-Zou Mau
- Graduate Institute of Metabolism and Obesity Sciences, College of Nutrition, Taipei Medical University, Taipei, 11031, Taiwan
| | - Yang-Ching Chen
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei, 11031, Taiwan.,Graduate Institute of Metabolism and Obesity Sciences, College of Nutrition, Taipei Medical University, Taipei, 11031, Taiwan
| | - Yen-Hao Su
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, 11301, Taiwan.,Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, 23561, Taiwan.,Department of General Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11301, Taiwan.,TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, 11031, Taiwan
| | - Hsin-An Chen
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, 11301, Taiwan.,Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, 23561, Taiwan.,Department of General Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11301, Taiwan.,TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, 11031, Taiwan
| | - Shih-Yi Huang
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei, 11031, Taiwan.,Graduate Institute of Metabolism and Obesity Sciences, College of Nutrition, Taipei Medical University, Taipei, 11031, Taiwan.,Nutrition Research Center, Taipei Medical University Hospital, Taipei, 11031, Taiwan
| | - Jung-Su Chang
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei, 11031, Taiwan. .,Graduate Institute of Metabolism and Obesity Sciences, College of Nutrition, Taipei Medical University, Taipei, 11031, Taiwan. .,Nutrition Research Center, Taipei Medical University Hospital, Taipei, 11031, Taiwan.
| | - Ching-Feng Chiu
- Graduate Institute of Metabolism and Obesity Sciences, College of Nutrition, Taipei Medical University, Taipei, 11031, Taiwan. .,Nutrition Research Center, Taipei Medical University Hospital, Taipei, 11031, Taiwan. .,TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
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Ferroptosis: A New Promising Target for Lung Cancer Therapy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:8457521. [PMID: 34616505 PMCID: PMC8487823 DOI: 10.1155/2021/8457521] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 08/16/2021] [Accepted: 09/15/2021] [Indexed: 12/21/2022]
Abstract
Ferroptosis is a new type of regulatory cell death that differs from autophagy, apoptosis, necrosis, and pyroptosis; it is caused primarily by the accumulation of iron and lipid peroxides in the cell. Studies have shown that many classical signaling pathways and biological processes are involved in the process of ferroptosis. In recent years, investigations have revealed that ferroptosis plays a crucial role in the progression of tumors, especially lung cancer. In particular, inducing ferroptosis in cells can inhibit the growth of tumor cells, thereby reversing tumorigenesis. In this review, we summarize the characteristics of ferroptosis from its underlying basis and role in lung cancer and provide possible applications for it in lung cancer therapies.
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Wu SY, Lin KC, Lawal B, Wu ATH, Wu CZ. MXD3 as an onco-immunological biomarker encompassing the tumor microenvironment, disease staging, prognoses, and therapeutic responses in multiple cancer types. Comput Struct Biotechnol J 2021; 19:4970-4983. [PMID: 34584637 PMCID: PMC8441106 DOI: 10.1016/j.csbj.2021.08.047] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 08/28/2021] [Accepted: 08/30/2021] [Indexed: 02/07/2023] Open
Abstract
MAX dimerization (MXD) protein 3 (MXD3) is a member of the MXD family of basic-helix-loop-helix-leucine-zipper (bHLHZ) transcription factors that plays pivotal roles in cell cycle progression and cell proliferation. However, there is insufficient scientific evidence on the pathogenic roles of MXD3 in various cancers and whether MXD3 plays a role in the immuno-oncology context of the tumor microenvironment, pathogenesis, prognosis, and therapeutic response of different tumors through certain common molecular mechanisms; thus, we saw a need to conduct the present in silico pan-cancer study. Using various computational tools, we interrogated the role of MXD3 in tumor immune infiltration, immune evasion, tumor progression, therapy response, and prognosis of cohorts from various cancer types. Our results indicated that MXD3 was aberrantly expressed in almost all The Cancer Genome Atlas (TCGA) cancer types and subtypes and was associated with the tumor stage, metastasis, and worse prognoses of various cohorts. Our results also suggested that MXD3 is associated with tumor immune evasion via different mechanisms involving T-cell exclusion in different cancer types and by tumor infiltration of immune cells in thymoma (THYM), liver hepatocellular carcinoma (LIHC), and head and neck squamous cell carcinoma (HNSC). Methylation of MXD3 was inversely associated with messenger (m)RNA expression levels and mediated dysfunctional T-cell phenotypes and worse prognoses of cohorts from different cancer types. Finally, we found that genetic alterations and oncogenic features of MXD3 were concomitantly associated with deregulation of the DBN1, RAB24, SLC34A1, PRELID1, LMAN2, F12, GRK6, RGS14, PRR7, and PFN3 genes and were connected to phospholipid transport and ion homeostasis. Our results also suggested that MXD3 expression is associated with immune or chemotherapeutic outcomes in various cancers. In addition, higher MXD3 expression levels were associated with decreased sensitivity of cancer cell lines to several mitogen-activated protein kinase kinase (MEK) inhibitors but led to increased activities of other kinase inhibitors, including Akt inhibitors. Interestingly, MXD3 exhibited higher predictive power for response outcomes and overall survival of immune checkpoint blockade sub-cohorts than three of seven standardized biomarkers. Altogether, our study strongly suggests that MXD3 is an immune-oncogenic molecule and could serve as a biomarker for cancer detection, prognosis, therapeutic design, and follow-up.
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Affiliation(s)
- Szu-Yuan Wu
- Department of Food Nutrition and Health Biotechnology, College of Medical and Health Science, Asia University, Taichung, Taiwan.,Big Data Center, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan.,Division of Radiation Oncology, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan.,Department of Healthcare Administration, College of Medical and Health Science, Asia University, Taichung, Taiwan.,Graduate Institute of Business Administration, Fu Jen Catholic University, New Taipei City, Taiwan.,Centers for Regional Anesthesia and Pain Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.,Cancer Center, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan
| | - Kuan-Chou Lin
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan.,Division of Oral and Maxillofacial Surgery, Department of Dentistry, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Bashir Lawal
- Graduate Institute for Cancer Biology & Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.,PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan
| | - Alexander T H Wu
- The PhD Program of Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.,Clinical Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan.,Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.,Taipei Heart Institute (THI), Taipei Medical University, Taipei, Taiwan
| | - Ching-Zong Wu
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Dentistry, Taipei Medical University Hospital, Taipei, Taiwan.,Department of Dentistry, Lotung Poh-Ai hospital, Yilan, Taiwan
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33
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Ren Z, Hu M, Wang Z, Ge J, Zhou X, Zhang G, Zheng H. Ferroptosis-Related Genes in Lung Adenocarcinoma: Prognostic Signature and Immune, Drug Resistance, Mutation Analysis. Front Genet 2021; 12:672904. [PMID: 34434214 PMCID: PMC8381737 DOI: 10.3389/fgene.2021.672904] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 05/20/2021] [Indexed: 12/25/2022] Open
Abstract
It is reported that ferroptosis has close relation with tumorigenesis and drug resistance. However, the clinical significance of ferroptosis in lung adenocarcinoma (LUAD) remains elusive, and the potential targets for ferroptosis-based treatment are limited. In this study, we constructed a 15-gene prognostic signature predicting overall survival based on ferroptosis-related genes (ferroptosis driver genes VDAC2, GLS2, FLT3, TLR4, PHKG2, phosphogluconate dehydrogenase (PGD), PANX1, KRAS, PEBP1, ALOX15, and ALOX12B, and suppressor genes ACSL3, CISD1, FANCD2, and SLC3A2) in The Cancer Genome Atlas (TCGA)-LUAD cohort. The signature’s predictive ability was validated in the GSE68465 and GSE72094 cohorts by survival analysis and independent prognostic analysis with clinical features. Nomograms were provided for clinical reference. Functional analysis revealed that ferroptosis was closely related to cell cycle, cell metabolism, and immune pathways. Pan-cancer analysis comprehensively analyzed these 15 genes in 33 cancer types, indicating that the heterogeneity of 15 genes was evident across different cancer types. Besides, these genes were critical regulators modulating drug resistance, tumor microenvironment infiltration, and cancer stemness. Then, we screened 10 genes (TLR4, PHKG2, PEBP1, GLS2, FLT3, ALOX15, ACSL3, CISD1, FANCD2, and SLC3A2) as potential targets for further research because their biological functions in ferroptosis were consistent with their prognostic significance. Somatic mutation and copy number variation analysis revealed that the alteration rates of KRAS, PGD, and ALOX15 were more than 1% and significantly associated with overall survival in LUAD. Moreover, the expression of KRAS and PGD was positively related to tumor mutation burden, indicating that KRAS and PGD could serve as novel biomarkers for predicting immunotherapy response rate. Our study identified and validated a ferroptosis-related gene signature for LUAD, provided a 10-gene set for future research, and screened KRAS and PGD as potential novel immunotherapy biomarkers.
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Affiliation(s)
- Ziyuan Ren
- Basic Medical School, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Minghui Hu
- Clinical Lab, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zhonglin Wang
- Department of Mathematics, University of California, Irvine, Irvine, CA, United States
| | - Junpeng Ge
- Department of Biology Engineering, Shandong Jianzhu University, Jinan, China
| | - Xiaoyan Zhou
- Clinical Lab, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Guoming Zhang
- Basic Medical School, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Hongying Zheng
- Clinical Lab, The Affiliated Hospital of Qingdao University, Qingdao, China
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Li H, Xia X, Tan X, Zang J, Wang Z, Ei-Seedi HR, Du M. Advancements of nature nanocage protein: preparation, identification and multiple applications of ferritins. Crit Rev Food Sci Nutr 2021; 62:7117-7128. [PMID: 33860692 DOI: 10.1080/10408398.2021.1911925] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Ferritin is an important iron storage protein, which is widely existed in all forms of life. Ferritin can regulate iron homeostasis when iron ions are lacking or enriched in the body, so as to avoid iron deficiency diseases and iron poisoning. Ferritin presents a hollow nanocage, which can store ions or other small molecular substances in the cavity. Therefore, ferritin shows its potential as a functional nanomaterial that can deliver nutrients or drugs in a targeted manner to improve bioavailability. Due to the special structure, the research on ferritin has attracted more and more attention in recent years. In this paper, the structural characteristics of ferritin were introduced, and the natural purification and prokaryotic expression methods of ferritin from different sources were described. At the same time, ferritin can bind to small molecules, so that it has the activity of small molecules, to construct a new type of ferritin. As a result, ferritin plays an important role as a nutrient substance, in targeted transport, and disease monitoring, etc. In conclusion, the yield of ferritin can be improved by means of molecular biology. Meanwhile, molecular modification can be used to make ferritin have unique activity and function, which lays a foundation for subsequent research. HighlightsThe molecular and structural properties of ferritins were clearly described.Isolation and purification technologies of ferritin were compared.Characterization, functions and molecular modifications mechanism of ferritin were reviewed.The applications of ferritin in pharmaceutical and food industry were prospected.
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Affiliation(s)
- Han Li
- School of Food Science and Technology, National Engineering Research Center of Seafood, Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, China
| | - Xiaoyu Xia
- School of Food Science and Technology, National Engineering Research Center of Seafood, Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, China
| | - Xiaoyi Tan
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Jiachen Zang
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Zhenyu Wang
- School of Food Science and Technology, National Engineering Research Center of Seafood, Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, China
| | - Hesham R Ei-Seedi
- Department of Medicinal Chemistry, Biomedical Centre, Uppsala University, Uppsala, Sweden
| | - Ming Du
- School of Food Science and Technology, National Engineering Research Center of Seafood, Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, China
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Onco-Receptors Targeting in Lung Cancer via Application of Surface-Modified and Hybrid Nanoparticles: A Cross-Disciplinary Review. Processes (Basel) 2021. [DOI: 10.3390/pr9040621] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Lung cancer is among the most prevalent and leading causes of death worldwide. The major reason for high mortality is the late diagnosis of the disease, and in most cases, lung cancer is diagnosed at fourth stage in which the cancer has metastasized to almost all vital organs. The other reason for higher mortality is the uptake of the chemotherapeutic agents by the healthy cells, which in turn increases the chances of cytotoxicity to the healthy body cells. The complex pathophysiology of lung cancer provides various pathways to target the cancerous cells. In this regard, upregulated onco-receptors on the cell surface of tumor including epidermal growth factor receptor (EGFR), integrins, transferrin receptor (TFR), folate receptor (FR), cluster of differentiation 44 (CD44) receptor, etc. could be exploited for the inhibition of pathways and tumor-specific drug targeting. Further, cancer borne immunological targets like T-lymphocytes, myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and dendritic cells could serve as a target site to modulate tumor activity through targeting various surface-expressed receptors or interfering with immune cell-specific pathways. Hence, novel approaches are required for both the diagnosis and treatment of lung cancers. In this context, several researchers have employed various targeted delivery approaches to overcome the problems allied with the conventional diagnosis of and therapy methods used against lung cancer. Nanoparticles are cell nonspecific in biological systems, and may cause unwanted deleterious effects in the body. Therefore, nanodrug delivery systems (NDDSs) need further advancement to overcome the problem of toxicity in the treatment of lung cancer. Moreover, the route of nanomedicines’ delivery to lungs plays a vital role in localizing the drug concentration to target the lung cancer. Surface-modified nanoparticles and hybrid nanoparticles have a wide range of applications in the field of theranostics. This cross-disciplinary review summarizes the current knowledge of the pathways implicated in the different classes of lung cancer with an emphasis on the clinical implications of the increasing number of actionable molecular targets. Furthermore, it focuses specifically on the significance and emerging role of surface functionalized and hybrid nanomaterials as drug delivery systems through citing recent examples targeted at lung cancer treatment.
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Transferrin receptor regulates malignancies and the stemness of hepatocellular carcinoma-derived cancer stem-like cells by affecting iron accumulation. PLoS One 2020; 15:e0243812. [PMID: 33351833 PMCID: PMC7755206 DOI: 10.1371/journal.pone.0243812] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 11/26/2020] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Iron metabolism is essential because it plays regulatory roles in various physiological and pathological processes. Disorders of iron metabolism balance are related to various cancers, including hepatocellular carcinoma. Cancer stem-like cells (CSCs) exert critical effects on chemotherapy failure, cancer metastasis, and subsequent disease recurrence and relapse. However, little is known about how iron metabolism affects liver CSCs. Here, we investigated the expression of transferrin receptor 1 (TFR1) and ferroportin (FPN), two iron importers, and an upstream regulator, iron regulatory protein 2 (IRP2), in liver hepatocellular carcinoma (LIHC) and related CSCs. METHODS The expression levels of TFR1, FPN and IRP2 were analysed using the GEPIA database. CSCs were derived from parental LIHC cells cultured in serum-free medium. After TFR1 knockdown, ROS accumulation and malignant behaviours were measured. The CCK-8 assay was performed to detect cell viability after TFR1 knockdown and erastin treatment. RESULTS TFR1 expression was upregulated in LIHC tissue and CSCs derived from LIHC cell lines, prompting us to investigate the roles of TFR1 in regulating CSCs. Knockdown of TFR1 expression decreased iron accumulation and inhibited malignant behaviour. Knockdown of TFR1 expression decreased reactive oxygen species (ROS) accumulation induced by erastin treatment and maintained mitochondrial function, indicating that TFR1 is critical in regulating erastin-induced cell death in CSCs. Additionally, knockdown of TFR1 expression decreased sphere formation by decreasing iron accumulation in CSCs, indicating a potential role for TFR1 in maintaining stemness. CONCLUSION These findings, which revealed TFR1 as a critical regulator of LIHC CSCs in malignant behaviour and stemness that functions by regulating iron accumulation, may have implications to improve therapeutic approaches.
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Khan A, Singh P, Srivastava A. Iron: Key player in cancer and cell cycle? J Trace Elem Med Biol 2020; 62:126582. [PMID: 32673942 DOI: 10.1016/j.jtemb.2020.126582] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Revised: 12/31/2019] [Accepted: 06/09/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Iron is an essential element for growth and metabolic activities of all living organisms but remains in its oxyhydroxide ferric ion form in the surrounding. Unavailability of iron in soluble ferrous form led to development of specific pathways and machinery in different organisms to make it available for use and maintain its homeostasis. Iron homeostasis is essential as under different circumstances iron in excess as well as deprivation leads to different pathological conditions in human. OBJECTIVE This review highlights the current findings related to iron excess as well as deprivation with regards to cellular proliferation. CONCLUSIONS Iron excess is extensively associated with different types of cancers viz. colorectal cancer, breast cancer etc. by producing an oxidative stressed condition and alteration of immune system. Ironically its deprivation also results in anaemic conditions and leads to cell cycle arrest at different phases with mechanism yet to be explored. Iron deprivation arrests cell cycle at G1/S and in some cases at G2/M checkpoints resulting in growth arrest. However, in some cases iron overload arrests cell cycle at G1 phase by blocking certain signalling pathways. Certain natural and synthetic iron chelators are being explored from few decades to combat diseases caused by alteration in iron homeostasis.
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Affiliation(s)
- Azmi Khan
- Department of Life Science, School of Earth, Biological and Environmental Sciences, Central University of South Bihar, Gaya, Bihar, India
| | - Pratika Singh
- Department of Life Science, School of Earth, Biological and Environmental Sciences, Central University of South Bihar, Gaya, Bihar, India
| | - Amrita Srivastava
- Department of Life Science, School of Earth, Biological and Environmental Sciences, Central University of South Bihar, Gaya, Bihar, India.
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38
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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: 29] [Impact Index Per Article: 5.8] [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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Jaganjac M, Milkovic L, Sunjic SB, Zarkovic N. The NRF2, Thioredoxin, and Glutathione System in Tumorigenesis and Anticancer Therapies. Antioxidants (Basel) 2020; 9:E1151. [PMID: 33228209 PMCID: PMC7699519 DOI: 10.3390/antiox9111151] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 11/16/2020] [Accepted: 11/17/2020] [Indexed: 12/24/2022] Open
Abstract
Cancer remains an elusive, highly complex disease and a global burden. Constant change by acquired mutations and metabolic reprogramming contribute to the high inter- and intratumor heterogeneity of malignant cells, their selective growth advantage, and their resistance to anticancer therapies. In the modern era of integrative biomedicine, realizing that a personalized approach could benefit therapy treatments and patients' prognosis, we should focus on cancer-driving advantageous modifications. Namely, reactive oxygen species (ROS), known to act as regulators of cellular metabolism and growth, exhibit both negative and positive activities, as do antioxidants with potential anticancer effects. Such complexity of oxidative homeostasis is sometimes overseen in the case of studies evaluating the effects of potential anticancer antioxidants. While cancer cells often produce more ROS due to their increased growth-favoring demands, numerous conventional anticancer therapies exploit this feature to ensure selective cancer cell death triggered by excessive ROS levels, also causing serious side effects. The activation of the cellular NRF2 (nuclear factor erythroid 2 like 2) pathway and induction of cytoprotective genes accompanies an increase in ROS levels. A plethora of specific targets, including those involved in thioredoxin (TRX) and glutathione (GSH) systems, are activated by NRF2. In this paper, we briefly review preclinical research findings on the interrelated roles of the NRF2 pathway and TRX and GSH systems, with focus given to clinical findings and their relevance in carcinogenesis and anticancer treatments.
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Affiliation(s)
| | | | | | - Neven Zarkovic
- Laboratory for Oxidative Stress, Division of Molecular Medicine, Rudjer Boskovic Institute, Bijenicka 54, 10000 Zagreb, Croatia; (M.J.); (L.M.); (S.B.S.)
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40
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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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Wu J, Ma L, Wang J, Qiao Y. [Mechanism of Ferroptosis and Its Research Progress in Lung Cancer]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2020; 23:811-817. [PMID: 32758348 PMCID: PMC7519954 DOI: 10.3779/j.issn.1009-3419.2020.104.16] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
铁死亡是近年来发现的一种铁依赖性的程序性细胞死亡，这种死亡是脂质过氧化物和活性氧堆积引起的。而肺癌作为病死率最高的恶性肿瘤之一，关于肺癌中铁死亡的研究甚少。本文中我们综述了肺癌中铁死亡受抑制的研究进展，从铁死亡发生的不同途径来解释肺癌中铁死亡受抑制现象。此外，诱导铁死亡治疗癌症越来越受到重视，本文中我们介绍了四种铁死亡激活剂以及铁死亡治疗肺癌的新展望，以期为肺癌治疗提供新的思路。
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Affiliation(s)
- Jinming Wu
- Public Health School, Shanghai Jiaotong University, Shanghai 200025, China
| | - Lifang Ma
- Shanghai Institute of Thoracic Tumors, Shanghai Chest Hospital, Shanghai 200030, China
| | - Jiayi Wang
- Shanghai Institute of Thoracic Tumors, Shanghai Chest Hospital, Shanghai 200030, China
| | - Yongxia Qiao
- Public Health School, Shanghai Jiaotong University, Shanghai 200025, China
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Che J, Yang J, Zhao B, Zhang G, Wang L, Peng S, Shang P. The Effect of Abnormal Iron Metabolism on Osteoporosis. Biol Trace Elem Res 2020; 195:353-365. [PMID: 31473898 DOI: 10.1007/s12011-019-01867-4] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 08/08/2019] [Indexed: 12/16/2022]
Abstract
Iron is one of the important trace elements in life activities. Abnormal iron metabolism increases the incidence of many skeletal diseases, especially for osteoporosis. Iron metabolism plays a key role in the bone homeostasis. Disturbance of iron metabolism not only promotes osteoclast differentiation and apoptosis of osteoblasts but also inhibits proliferation and differentiation of osteoblasts, which eventually destroys the balance of bone remodeling. The strength and density of bone can be weakened by the disordered iron metabolism, which increases the incidence of osteoporosis. Clinically, compounds or drugs that regulate iron metabolism are used for the treatment of osteoporosis. The goal of this review summarizes the new progress on the effect of iron overload or deficiency on osteoporosis and the mechanism of disordered iron metabolism on osteoporosis. Explaining the relationship of iron metabolism with osteoporosis may provide ideas for clinical treatment and development of new drugs.
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Affiliation(s)
- Jingmin Che
- Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen, 518057, Guangdong, China
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi, China
- Key Laboratory for Space Bioscience and Biotechnology, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi, China
| | - Jiancheng Yang
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi, China
- Key Laboratory for Space Bioscience and Biotechnology, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi, China
| | - Bin Zhao
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi, China
- Key Laboratory for Space Bioscience and Biotechnology, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi, China
| | - Ge Zhang
- Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China
| | - Luyao Wang
- Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China
| | - Songlin Peng
- Department of Spine Surgery, Shenzhen People's Hospital, Shenzhen, 518000, Guangdong, China
| | - Peng Shang
- Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen, 518057, Guangdong, China.
- Key Laboratory for Space Bioscience and Biotechnology, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi, China.
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He Y, Gong R, Peng KW, Liu LZ, Sun LY, Wang HY. Lymphocyte-to-C-reactive protein ratio is a potential new prognostic biomarker for patients with lung cancer. Biomark Med 2020; 14:717-726. [PMID: 32643402 DOI: 10.2217/bmm-2019-0452] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Accepted: 04/20/2020] [Indexed: 12/18/2022] Open
Abstract
Aim: To compare and evaluate the prognostic value of various pretreatment combinations of inflammatory factors in patients with lung cancer (LC). Materials & methods: This study enrolled 1005 patients with LC and categorized into a discovery cohort and a validation cohort. Results: A combination of Lymphocyte-to-C-reactive protein levels (LCR) demonstrated the highest correlation with poor first-line progression-free survival (PFS) and overall survival (OS) (p < 0.05), but not disease-free survival (p > 0.05) compared with other parameters in LC patients. Decreased preoperative LCR was an independent prognostic factor for first-line PFS and OS (p < 0.05), but not disease-free survival (p > 0.05) in patients. Conclusion: Pretreatment LCR is a promising biomarker for first-line PFS and OS in patients with LC.
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Affiliation(s)
- Yuan He
- Department of Ultrasound & Electrocardiogram, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, PR China
| | - Rui Gong
- Department of Healthcare, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, PR China
| | - Kun-Wei Peng
- Department of VIP region, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, PR China
| | - Li-Zhen Liu
- Department of Ultrasound & Electrocardiogram, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, PR China
| | - Li-Yue Sun
- Department of Molecular Diagnostics, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, PR China
| | - Hai-Yun Wang
- Department of Molecular Diagnostics, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, PR China
- Heart Center, Institute of Pediatrics, Guangzhou Women & Children's Medical Center, Guangzhou, PR China
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Bossé Y, Li Z, Xia J, Manem V, Carreras-Torres R, Gabriel A, Gaudreault N, Albanes D, Aldrich MC, Andrew A, Arnold S, Bickeböller H, Bojesen SE, Brennan P, Brunnstrom H, Caporaso N, Chen C, Christiani DC, Field JK, Goodman G, Grankvist K, Houlston R, Johansson M, Johansson M, Kiemeney LA, Lam S, Landi MT, Lazarus P, Le Marchand L, Liu G, Melander O, Rennert G, Risch A, Rosenberg SM, Schabath MB, Shete S, Song Z, Stevens VL, Tardon A, Wichmann HE, Woll P, Zienolddiny S, Obeidat M, Timens W, Hung RJ, Joubert P, Amos CI, McKay JD. Transcriptome-wide association study reveals candidate causal genes for lung cancer. Int J Cancer 2020; 146:1862-1878. [PMID: 31696517 PMCID: PMC7008463 DOI: 10.1002/ijc.32771] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2019] [Revised: 10/09/2019] [Accepted: 10/10/2019] [Indexed: 12/17/2022]
Abstract
We have recently completed the largest GWAS on lung cancer including 29,266 cases and 56,450 controls of European descent. The goal of our study has been to integrate the complete GWAS results with a large-scale expression quantitative trait loci (eQTL) mapping study in human lung tissues (n = 1,038) to identify candidate causal genes for lung cancer. We performed transcriptome-wide association study (TWAS) for lung cancer overall, by histology (adenocarcinoma, squamous cell carcinoma and small cell lung cancer) and smoking subgroups (never- and ever-smokers). We performed replication analysis using lung data from the Genotype-Tissue Expression (GTEx) project. DNA damage assays were performed in human lung fibroblasts for selected TWAS genes. As expected, the main TWAS signal for all histological subtypes and ever-smokers was on chromosome 15q25. The gene most strongly associated with lung cancer at this locus using the TWAS approach was IREB2 (pTWAS = 1.09E-99), where lower predicted expression increased lung cancer risk. A new lung adenocarcinoma susceptibility locus was revealed on 9p13.3 and associated with higher predicted expression of AQP3 (pTWAS = 3.72E-6). Among the 45 previously described lung cancer GWAS loci, we mapped candidate target gene for 17 of them. The association AQP3-adenocarcinoma on 9p13.3 was replicated using GTEx (pTWAS = 6.55E-5). Consistent with the effect of risk alleles on gene expression levels, IREB2 knockdown and AQP3 overproduction promote endogenous DNA damage. These findings indicate genes whose expression in lung tissue directly influences lung cancer risk.
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Affiliation(s)
- Yohan Bossé
- Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Quebec City, Canada
- Department of Molecular Medicine, Laval University, Quebec City, Canada
| | - Zhonglin Li
- Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Quebec City, Canada
| | - Jun Xia
- Baylor College of Medicine, The Institute for Clinical and Translational Research, Houston, TX
| | - Venkata Manem
- Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Quebec City, Canada
| | | | - Aurélie Gabriel
- International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Nathalie Gaudreault
- Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Quebec City, Canada
| | - Demetrius Albanes
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
| | - Melinda C Aldrich
- Thoracic Surgery, Division of Epidemiology, Vanderbilt University Medical Center, Nashville, TN
| | - Angeline Andrew
- Department of Neurology, Dartmouth-Hitchcock Medical Center, Lebanon, NH
| | - Susanne Arnold
- Markey Cancer Center, University of Kentucky, Lexington, KY
| | - Heike Bickeböller
- Department of Genetic Epidemiology, University Medical Center Goettingen, Goettingen, Germany
| | - Stig E Bojesen
- Department of Clinical Biochemistry, Copenhagen University Hospital, Copenhagen, Denmark
| | - Paul Brennan
- International Agency for Research on Cancer, World Health Organization, Lyon, France
| | | | - Neil Caporaso
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
| | - Chu Chen
- Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - David C Christiani
- Program in Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
| | - John K Field
- Molecular and Clinical Cancer Medicine, Roy Castle Lung Cancer Research Programme, The University of Liverpool Institute of Translational Medicine, Liverpool, United Kingdom
| | - Gary Goodman
- Public Health Sciences Division, Swedish Cancer Institute, Seattle, WA
| | - Kjell Grankvist
- Department of Medical Biosciences, Umeå University, Umea, Sweden
| | - Richard Houlston
- German Research Center for Environmental Health, Institute for Cancer Research, London, United Kingdom
| | - Mattias Johansson
- International Agency for Research on Cancer, World Health Organization, Lyon, France
| | | | - Lambertus A Kiemeney
- Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Stephen Lam
- Department of Integrative Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada
| | | | - Philip Lazarus
- Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Pullman, WA
| | - Loic Le Marchand
- Department of Epidemiology, University of Hawaii Cancer Center, Honolulu, HI
| | - Geoffrey Liu
- Epidemiology Division, Princess Margaret Cancer Center, Toronto, ON, Canada
| | | | - Gadi Rennert
- Technion Faculty of Medicine, Carmel Medical Center, Haifa, Israel
| | - Angela Risch
- Cancer Center Cluster Salzburg at PLUS, Department of Molecular Biology, University of Salzburg, Salzburg, Austria
| | - Susan M Rosenberg
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX
| | - Matthew B Schabath
- Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Sanjay Shete
- Epidemiology, The University of Texas, MD Anderson Cancer Center, Houston, TX
| | - Zhuoyi Song
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX
| | | | - Adonina Tardon
- Faculty of Medicine, University of Oviedo and CIBERESP, Oviedo, Spain
| | - H-Erich Wichmann
- Institute of Epidemiology, Helmholtz Center Munich, Oberschleißheim, Germany
| | - Penella Woll
- Academic Unit of Clinical Oncology, University of Sheffield, Sheffield, United Kingdom
| | | | - Ma'en Obeidat
- The University of British Columbia Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, BC, Canada
| | - Wim Timens
- Department of Pathology and Medical Biology, GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Rayjean J Hung
- Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada
| | - Philippe Joubert
- Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Quebec City, Canada
| | - Christopher I Amos
- Baylor College of Medicine, The Institute for Clinical and Translational Research, Houston, TX
| | - James D McKay
- International Agency for Research on Cancer, World Health Organization, Lyon, France
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Forciniti S, Greco L, Grizzi F, Malesci A, Laghi L. Iron Metabolism in Cancer Progression. Int J Mol Sci 2020; 21:2257. [PMID: 32214052 PMCID: PMC7139548 DOI: 10.3390/ijms21062257] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 03/21/2020] [Accepted: 03/22/2020] [Indexed: 12/11/2022] Open
Abstract
Iron is indispensable for cell metabolism of both normal and cancer cells. In the latter, several disruptions of its metabolism occur at the steps of tumor initiation, progression and metastasis. Noticeably, cancer cells require a large amount of iron, and exhibit a strong dependence on it for their proliferation. Numerous iron metabolism-related proteins and signaling pathways are altered by iron in malignancies, displaying the pivotal role of iron in cancer. Iron homeostasis is regulated at several levels, from absorption by enterocytes to recycling by macrophages and storage in hepatocytes. Mutations in HFE gene alter iron homeostasis leading to hereditary hemochromatosis and to an increased cancer risk because the accumulation of iron induces oxidative DNA damage and free radical activity. Additionally, the iron capability to modulate immune responses is pivotal in cancer progression. Macrophages show an iron release phenotype and potentially deliver iron to cancer cells, resulting in tumor promotion. Overall, alterations in iron metabolism are among the metabolic and immunological hallmarks of cancer, and further studies are required to dissect how perturbations of this element relate to tumor development and progression.
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Affiliation(s)
- Stefania Forciniti
- Humanitas Clinical and Research Center, IRCCS, Department of Gastroenterology—Laboratory of Molecular Gastroenterology, Rozzano, 20089 Milan, Italy; (S.F.); (L.G.)
| | - Luana Greco
- Humanitas Clinical and Research Center, IRCCS, Department of Gastroenterology—Laboratory of Molecular Gastroenterology, Rozzano, 20089 Milan, Italy; (S.F.); (L.G.)
| | - Fabio Grizzi
- Department of Immunology and Inflammation, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano, 20089 Milan, Italy;
| | - Alberto Malesci
- Humanitas Clinical and Research Center, IRCCS, Department of Gastroenterology, Rozzano, 20089 Milan, Italy;
| | - Luigi Laghi
- Humanitas Clinical and Research Center, IRCCS, Department of Gastroenterology—Laboratory of Molecular Gastroenterology, Rozzano, 20089 Milan, Italy; (S.F.); (L.G.)
- Department of Medicine and Surgery, University of Parma, 43100 Parma, Italy
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Schnetz M, Meier JK, Rehwald C, Mertens C, Urbschat A, Tomat E, Akam EA, Baer P, Roos FC, Brüne B, Jung M. The Disturbed Iron Phenotype of Tumor Cells and Macrophages in Renal Cell Carcinoma Influences Tumor Growth. Cancers (Basel) 2020; 12:cancers12030530. [PMID: 32106629 PMCID: PMC7139531 DOI: 10.3390/cancers12030530] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 02/21/2020] [Accepted: 02/23/2020] [Indexed: 12/27/2022] Open
Abstract
Accumulating evidence suggests that iron homeostasis is disturbed in tumors. We aimed at clarifying the distribution of iron in renal cell carcinoma (RCC). Considering the pivotal role of macrophages for iron homeostasis and their association with poor clinical outcome, we investigated the role of macrophage-secreted iron for tumor progression by applying a novel chelation approach. We applied flow cytometry and multiplex-immunohistochemistry to detect iron-dependent markers and analyzed iron distribution with atomic absorption spectrometry in patients diagnosed with RCC. We further analyzed the functional significance of iron by applying a novel extracellular chelator using RCC cell lines as well as patient-derived primary cells. The expression of iron-regulated genes was significantly elevated in tumors compared to adjacent healthy tissue. Iron retention was detected in tumor cells, whereas tumor-associated macrophages showed an iron-release phenotype accompanied by enhanced expression of ferroportin. We found increased iron amounts in extracellular fluids, which in turn stimulated tumor cell proliferation and migration. In vitro, macrophage-derived iron showed pro-tumor functions, whereas application of an extracellular chelator blocked these effects. Our study provides new insights in iron distribution and iron-handling in RCC. Chelators that specifically scavenge iron in the extracellular space confirmed the importance of macrophage-secreted iron in promoting tumor growth.
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Affiliation(s)
- Matthias Schnetz
- Institute of Biochemistry I, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany; (M.S.); (J.K.M.); (C.R.); (C.M.); (B.B.)
| | - Julia K. Meier
- Institute of Biochemistry I, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany; (M.S.); (J.K.M.); (C.R.); (C.M.); (B.B.)
| | - Claudia Rehwald
- Institute of Biochemistry I, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany; (M.S.); (J.K.M.); (C.R.); (C.M.); (B.B.)
| | - Christina Mertens
- Institute of Biochemistry I, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany; (M.S.); (J.K.M.); (C.R.); (C.M.); (B.B.)
| | - Anja Urbschat
- Institute for Biomedicine, Aarhus University, C. F. Møllers Allé 6, 8000 Aarhus, Denmark;
| | - Elisa Tomat
- Department of Chemistry and Biochemistry, University of Arizona, 1306 E. University Blvd., Tucson, AZ 85721-0041, USA; (E.T.); (E.A.A.)
| | - Eman A. Akam
- Department of Chemistry and Biochemistry, University of Arizona, 1306 E. University Blvd., Tucson, AZ 85721-0041, USA; (E.T.); (E.A.A.)
| | - Patrick Baer
- Division of Nephrology, Department of Internal Medicine III, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany;
| | - Frederik C. Roos
- Clinic of Urology, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany;
| | - Bernhard Brüne
- Institute of Biochemistry I, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany; (M.S.); (J.K.M.); (C.R.); (C.M.); (B.B.)
- German Cancer Consortium (DKTK), partner site Frankfurt/Mainz, 60590 Frankfurt am Main, Germany
- Frankfurt Cancer Institute, Goethe-University Frankfurt, 60596 Frankfurt am Main, Germany
- Project Group Translational Medicine and Pharmacology TMP, Fraunhofer Institute for Molecular Biology and Applied Ecology, 60596 Frankfurt am Main, Germany
| | - Michaela Jung
- Institute of Biochemistry I, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany; (M.S.); (J.K.M.); (C.R.); (C.M.); (B.B.)
- Correspondence: ; Tel.: +49-69-6301-6931; Fax: +49-69-6301-4203
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Jaganjac M, Borovic Sunjic S, Zarkovic N. Utilizing Iron for Targeted Lipid Peroxidation as Anticancer Option of Integrative Biomedicine: A Short Review of Nanosystems Containing Iron. Antioxidants (Basel) 2020; 9:E191. [PMID: 32106528 PMCID: PMC7139573 DOI: 10.3390/antiox9030191] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 02/19/2020] [Accepted: 02/21/2020] [Indexed: 01/07/2023] Open
Abstract
Traditional concepts of life sciences consider oxidative stress as a fundamental process of aging and various diseases including cancer, whereas traditional medicine recommends dietary intake of iron to support physiological functions of the organism. However, due to its strong pro-oxidative capacity, if not controlled well, iron can trigger harmful oxidative stress manifested eventually by toxic chain reactions of lipid peroxidation. Such effects of iron are considered to be major disadvantages of uncontrolled iron usage, although ferroptosis seems to be an important defense mechanism attenuating cancer development. Therefore, a variety of iron-containing nanoparticles were developed for experimental radio-, chemo-, and photodynamic as well as magnetic dynamic nanosystems that alter redox homeostasis in cancer cells. Moreover, studies carried over recent decades have revealed that even the end products of lipid peroxidation, represented by 4-hydroxynonenal (4-HNE), could have desirable effects even acting as kinds of selective anticancer substances produced by non-malignant cells for defense again invading cancer. Therefore, advanced nanotechnologies should be developed for using iron to trigger targeted lipid peroxidation as an anticancer option of integrative biomedicine.
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Affiliation(s)
- Morana Jaganjac
- Qatar Analytics & BioResearch Laboratory, Anti Doping Laboratory Qatar, Doha, Qatar;
- Rudjer Boskovic Institute, Laboratory for Oxidative Stress, Division of Molecular Medicine, Bijenicka 54, 10000 Zagreb, Croatia;
| | - Suzana Borovic Sunjic
- Rudjer Boskovic Institute, Laboratory for Oxidative Stress, Division of Molecular Medicine, Bijenicka 54, 10000 Zagreb, Croatia;
| | - Neven Zarkovic
- Rudjer Boskovic Institute, Laboratory for Oxidative Stress, Division of Molecular Medicine, Bijenicka 54, 10000 Zagreb, Croatia;
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Huang W, Li W, Liu J, Hou J, Meng H. Ferritin expression in the periodontal tissues of primates. Eur J Histochem 2019; 63. [PMID: 31505926 PMCID: PMC6755262 DOI: 10.4081/ejh.2019.3046] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Accepted: 08/13/2019] [Indexed: 01/01/2023] Open
Abstract
Ferritin, an iron-binding protein, is composed of two subunits, ferritin heavy chain and ferritin light chain. It regulates many biological functions, such as proliferation, angiogenesis, and immunosuppression. The objective of this study was to determine the expression and distribution of ferritin in the periodontal tissues of primates. First, we assessed the expression of ferritin in primary cultured cells isolated from human periodontal tissues using the polymerase chain reaction and immunofluorescent staining in vitro. Second, we investigated the expression and distribution of ferritin in the periodontal tissues of Macaca fascicularis, human gingival tissues, and human gingival carcinoma tissues using immunohistochemistry in vivo. Both protein and mRNA of ferritin were constitutively present in human primary cultured cells, including those from the dental apical papilla, periodontal ligament, dental pulp, and gingival epithelium, as well as gingival fibroblasts. In M. fascicularis tissues, the immunohistochemical staining was particularly strong in blood vessel and mineralizing areas of the dental pulp and periodontal ligament. Ferritin heavy chain exhibited specific immunopositivity in the stratum basal of the epithelium in human gingival tissue, and strong immunostaining was found in peripheral regions of gingival carcinoma sites. Ferritin is constitutively present and widely distributed in the periodontal tissues of primates. Ferritin may play roles in epithelial proliferation, vascular angiogenesis, and mineralization in these tissues.
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Affiliation(s)
- Wenxue Huang
- Peking University School and Hospital of Stomatology.
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Ye J, Ma J, Liu C, Huang J, Wang L, Zhong X. A novel iron(II) phenanthroline complex exhibits anticancer activity against TFR1-overexpressing esophageal squamous cell carcinoma cells through ROS accumulation and DNA damage. Biochem Pharmacol 2019; 166:93-107. [PMID: 31078603 DOI: 10.1016/j.bcp.2019.05.013] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 05/07/2019] [Indexed: 12/24/2022]
Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most common and aggressive cancers worldwide, especially in China, with poor prognosis due to the lack of effective therapeutic strategies. Here, the anticancer effect and pharmacological mechanism of a newly synthesized Fe(II) phenanthroline complex was studied in ESCC. Our data showed that transferrin receptor 1 (TFR1) was specifically overexpressed in ESCC tissues compared to its expression in normal esophageal tissues, a finding further supported by public datasets. The newly synthesized Fe(II) complex was selectively transported into ESCC cells overexpressing TFR1 through TFR1-mediated endocytosis and exhibited anticancer activity in a dose-dependent manner. The mechanistic study elucidated that the Fe(II) complex caused cell cycle arrest at the G0/G1 phase by blocking the CDK4/6-cyclin D1 complex and induced mitochondria-mediated apoptosis. Furthermore, exposure to the Fe(II) complex led to excessive reactive oxygen species (ROS) accumulation by thioredoxin reductase (TrxR) inhibition and DNA double-strand breaks (DSBs), which in turn sequentially activated ATM, CHK1/2 and p53. Moreover, combination treatment with cisplatin and the Fe(II) complex exhibited a synergistic effect in ESCC cells. Taken together, our results initially suggest the potential application of the Fe(II) complex in ESCC chemotherapy, especially for patients with TFR1 overexpression.
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Affiliation(s)
- Jiecheng Ye
- Department of Pathology, Medical College, Jinan University, Guangzhou 510632, China; Guangdong Province Key Laboratory of Molecular Immunology and Antibody Engineering, Jinan University, Guangzhou 510632, China
| | - Jiwei Ma
- Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China
| | - Chan Liu
- Department of Pathology, Medical College, Jinan University, Guangzhou 510632, China; Guangdong Province Key Laboratory of Molecular Immunology and Antibody Engineering, Jinan University, Guangzhou 510632, China
| | - Jianxian Huang
- Department of Pathology, Medical College, Jinan University, Guangzhou 510632, China; Guangdong Province Key Laboratory of Molecular Immunology and Antibody Engineering, Jinan University, Guangzhou 510632, China
| | - Lihui Wang
- Department of Pathology, Medical College, Jinan University, Guangzhou 510632, China; Guangdong Province Key Laboratory of Molecular Immunology and Antibody Engineering, Jinan University, Guangzhou 510632, China.
| | - Xueyun Zhong
- Department of Pathology, Medical College, Jinan University, Guangzhou 510632, China; Guangdong Province Key Laboratory of Molecular Immunology and Antibody Engineering, Jinan University, Guangzhou 510632, China.
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50
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Lee S, Jeon H, Shim B. Prognostic Value of Ferritin-to-Hemoglobin Ratio in Patients with Advanced Non-Small-Cell Lung Cancer. J Cancer 2019; 10:1717-1725. [PMID: 31205527 PMCID: PMC6548010 DOI: 10.7150/jca.26853] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Accepted: 01/20/2019] [Indexed: 12/13/2022] Open
Abstract
Background: Among commonly used biomarkers that reflect overall health in patients with cancer, hemoglobin is an iron-containing, oxygen-carrying protein in red blood cells, and serum ferritin is an iron-storage protein. This study investigated the ability of the ferritin-to-hemoglobin ratio to predict survival in patients with advanced non-small-cell lung cancer (NSCLC). Methods: The medical records of patients with pathologically confirmed advanced NSCLC were retrospectively reviewed. The ferritin level, hemoglobin level, and ferritin-to-hemoglobin ratio at the initiation of treatment were investigated. After descriptive analysis of the ferritin-to-hemoglobin ratio, the optimal diagnostic cutoff value for survival was determined using receiver operating characteristic analysis. After dichotomizing patients according to the optimal cutoff value, the prognostic effect of the ferritin-to-hemoglobin ratio was assessed. Overall survival (OS) was calculated using Kaplan-Meier analysis and compared using log-rank tests. Cox proportional hazards regression was used to evaluate the prognostic effect with respect to survival. Results: Of the enrolled patients, 91.3% had stage IV NSCLC, 42.0% had an Eastern Cooperative Oncology Group-performance status (ECOG-PS) score of 2, and 56.5% previously underwent systemic chemotherapy. The median OS of enrolled patients was 11.5 months. The range of the ferritin-to-hemoglobin ratio was 0.6-294.2, and the optimal cutoff value of the ferritin-to-hemoglobin ratio for survival was 13.0 (sensitivity, 58.5%; specificity, 80.0%; area under the curve = 0.68; P = 0.004). The median OS of patients with a low ferritin-to-hemoglobin ratio (<13.0) was 19.7 months, whereas that of patients with a high ferritin-to-hemoglobin ratio (≥13.0) was 8.5 months (P < 0.001). After eliminating confounding factors such as age, sex, ECOG-PS, histologic type, and C-reactive protein level, a high ferritin-to-hemoglobin ratio was significantly associated with poor survival. The multivariate proportional hazards model revealed that the ferritin-to-hemoglobin ratio was an independent prognostic marker for survival (hazard ratio, 1.91; 95% confidence interval, 1.27-2.88; P = 0.002). Conclusion: The ferritin-to-hemoglobin ratio, a potential parameter of tumor progression, was a significant prognostic factor for OS, with a direct correlation to survival time in patients with advanced NSCLC.
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Affiliation(s)
- Sookyung Lee
- Department of Clinical Oncology, College of Korean Medicine, Kyung Hee University
| | - Hyeonjin Jeon
- Department of Clinical Korean Medicine, Graduate School, Kyung Hee University
| | - Bumsang Shim
- Department of Pathology, College of Korean Medicine, Kyung Hee University
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