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Iron and cancer: recent insights
Open accessAbstract
Iron is an essential dietary element. However, the ability of iron to cycle between oxidized and reduced forms also renders it capable of contributing to free radical formation, which can have deleterious effects, including promutagenic effects that can potentiate tumor formation. Dysregulation of iron metabolism can increase cancer risk and promote tumor growth. Cancer cells exhibit an enhanced dependence on iron relative to their normal counterparts, a phenomenon we have termed iron addiction. Work conducted in the past few years has revealed new cellular processes and mechanisms that deepen our understanding of the link between iron and cancer. Control of iron efflux through the combined action of ferroportin, an iron efflux pump, and its regulator hepcidin appears to play an important role in tumorigenesis. Ferroptosis is a form of iron‐dependent cell death involving the production of reactive oxygen species. Specific mechanisms involved in ferroptosis, including depletion of glutathione and inhibition of glutathione peroxidase 4, have been uncovered. Ferritinophagy is a newly identified mechanism for degradation of the iron storage protein ferritin. Perturbations of mechanisms that control transcripts encoding proteins that regulate iron have been observed in cancer cells, including differences in miRNA, methylation, and acetylation. These new insights may ultimately provide new therapeutic opportunities for treating cancer.
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“cancer cells have a high demand for easily accessible labile Fe2+ for their survival and growth.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [23]
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“Ferroptosis is recognized as non-apoptotic mediated cell death, usually caused by irondependent lipid peroxidation (122, 123).”
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“Specifically, in clear cell ovarian cancers, RAS mutations [45] and c-MYC amplifications [46] are prominent in addition to PIK3CA and PTEN alterations [47] which is expected to lead to increased tumorigenic potential associated with “iron addiction” [48].”
BackgroundHu, H., Zhang, F., Sheng, Z., Tian, S., Li, G., Tang, S., Niu, Y., Yang, J., & Liu, Y. (2024) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2024.116295 · Cited by 29
Dietary sources of iron and vitamin B12: Is this the missing link in colorectal carcinogenesis?
Banjari, I., & Hjartåker, A. (2018) · Medical Hypotheses · doi:10.1016/j.mehy.2018.05.003 · Cited by 30
Mou, Y., Zhang, Y., Wu, J., Hu, B., Zhang, C., Duan, C., & Li, B. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00788 · Cited by 29
Jin, D., Hui, Y., Liu, D., Li, N., Leng, J., Wang, G., Wang, Q., & Lu, Z. (2024) · Functional & Integrative Genomics · doi:10.1007/s10142-024-01292-4 · Cited by 28
“The impact of ferroptosis underlying HCC has also been demonstrated (Manz et al. 2016; Mou et al. 2019; Nie et al. 2018).”
BackgroundTargeting iron metabolism in high-grade glioma with 68Ga-citrate PET/MR
Behr, S. C., Villanueva-Meyer, J. E., Li, Y., Wang, Y.-H., Wei, J., Moroz, A., Lee, J. K. L., Hsiao, J. C., Gao, K. T., Ma, W., et al. (2018) · JCI Insight · doi:10.1172/jci.insight.93999 · Cited by 28
Liu, J., Lou, C., Zhen, C., Wang, Y., Shang, P., & Lv, H. (2022) · Metallomics · doi:10.1093/mtomcs/mfac027 · Cited by 28
Zhao, J.-W., Zhao, W., Cui, X.-H., Xing, L., Shi, J.-C., & Yu, L. (2023) · Clinical & Translational Oncology · doi:10.1007/s12094-023-03269-4 · Cited by 30
“An iron metabolism disorder has also been linked to the growth and proliferation of tumor cells [13].”
Jiang, X., Zhang, C., Qi, S., Guo, S., Chen, Y., Du, E., Zhang, H., Wang, X., Liu, R., Qiao, B., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.12753 · Cited by 28
“Iron is an essential element for cell growth, as it is involved in DNA synthesis, energy metabolisms and other important cellular processes [18].”
BackgroundSong, K., Liu, X., Xu, H., Li, M., Zheng, Q., Qi, C., Wang, X., Liu, Y., Zheng, P., & Liu, J. (2024) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2024.171818 · Cited by 27
Hu, A., Li, L., Hu, C., Zhang, D., Wang, C., Jiang, Y., Zhang, M., Liang, C., Chen, W., Bo, Q., et al. (2018) · Biological Trace Element Research · doi:10.1007/s12011-018-1283-4 · Cited by 27
Leitch, H. A., Buckstein, R. J., Zhu, N. Y., Nevill, T. J., Yee, K. W. L., Leber, B. F., Keating, M., St‐Hilaire, È., Kumar, R., Delage, R., et al. (2018) · Leukemia Research · doi:10.1016/j.leukres.2018.09.005 · Cited by 27
Iron Metabolism in Liver Cancer Stem Cells
Recalcati, S., Correnti, M., Gammella, E., Raggi, C., Invernizzi, P., & Cairo, G. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00149 · Cited by 29
Lin, J., Wu, Y., Liang, X., Ji, M., Ying, H., Wang, X., Sun, X., Shao, C., Zhan, L., & Zhang, Y. (2018) · Molecular Carcinogenesis · doi:10.1002/mc.22920 · Cited by 26
“In this study, expression of TF was down-regulated in PC samples, which might be related to the dysregulation of iron metabolism in many cancer cells.(86) Future efforts are needed to identify the roles of these genes in the pathogenesis of PC.”
BackgroundIron in the Tumor Microenvironment
Vela, D. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-43093-1_3 · Cited by 27
Antineoplastic behavior of polydopamine nanoparticles prepared in different water/alcohol media
Nieto, C., Marcelo, G., Vega, M. A., & del Valle, E. M. M. (2020) · Colloids and Surfaces B Biointerfaces · doi:10.1016/j.colsurfb.2020.111506 · Cited by 26
“In addition, since cancer cells have a greater iron-dependence than normal cells [14, 15], the viability of the latter was not so reduced by the PD NPs cytotoxicity mediated by their Fe3+-loading capacity.”
BackgroundA narrative review of mechanisms of ferroptosis in cancer: new challenges and opportunities
Jiang, M., Hu, R., Yu, R., Tang, Y., & Li, J. (2021) · Annals of Translational Medicine · doi:10.21037/atm-21-4863 · Cited by 26
“Ann Transl Med 2021;9(20):1599 | https://dx.”
BackgroundChen, Y.-C., Li, W., Yang, Y., Zhong, R., Hu, H., Huang, C., Chen, J., Liang, L., & Liu, Y. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115541 · Cited by 26
Quantitative label-free imaging of iron-bound transferrin in breast cancer cells and tumors
Khoo, T. C., Tubbesing, K. E., Rudkouskaya, A., Rajoria, S., Sharikova, A. V., Barroso, M., & Khmaladze, A. T. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101617 · Cited by 25
“Increased expression of proteins that support iron import and transport, like the transferrin receptor (TfR), has been associated with rapidly proliferating cancer cells [2,4].”
BackgroundEndogenous doesn’t always mean innocuous: a scoping review of iron toxicity by inhalation
Morgan, J., Bell, R. G., & Jones, A. L. (2020) · Journal of Toxicology and Environmental Health Part B · doi:10.1080/10937404.2020.1731896 · Cited by 24
“2015) with increasing intracellular iron concentrations shown to promote ferroptosis, a nonapoptotic form of cell death characterized by reduced mitochondrial size with increased membrane density which is believed to occur via the iron-mediated accumulation of lipid peroxidation (Manz et al. 2016).”
BackgroundInfluentialMechanism and application of ferroptosis in colorectal cancer
Liu, Y., Zhang, Y., Zhang, Y., & Fan, Z. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.114102 · Cited by 24
Ginsenoside compound K induces ferroptosis via the FOXO pathway in liver cancer cells
Chen, J., Wang, Z., Fu, J., Cai, Y., Cheng, H., Cui, X., Sun, M., Liu, M., & Zhang, X. (2024) · BMC Complementary Medicine and Therapies · doi:10.1186/s12906-024-04471-9 · Cited by 27
“GPX4 degrades some small molecule per-oxides and lipid peroxides in the cell, such as catalyzing GSH to produce GSSG, thereby inhibiting lipid peroxidation [14].”
Chen, X., Tu, J., Ma, L., Huang, Y., Yang, C., & Yuan, X. (2022) · International Journal of General Medicine · doi:10.2147/ijgm.s354682 · Cited by 23
“As tumor cells typically have greater iron needs to sustain abnormal metabolism and aberrant proliferation, tumor tissues are over-reliance on iron for proliferation.(7,8) Recent studies indicate that induction of ferroptosis has appeared to be a promising therapeutic strategy, in particular, applicable for malignant…”
BackgroundMao, X., Calero‐Pérez, P., Montpeyó, D., Bruna, J., Yuste, V. J., Candiota, A. P., Lorenzo, J., Novio, F., & Ruiz‐Molina, D. (2022) · Nanomaterials · doi:10.3390/nano12071221 · Cited by 24
“In addition to exhibiting different internalization mechanisms, the increased demand for iron as an essential nutrient for various biochemical activities associated with cell growth and proliferation may also contribute to the higher internalization of Pt-Fe NCPs [52].”
BackgroundCheng, G., Zielonka, J., Hardy, M., Ouari, O., Chitambar, C. R., Dwinell, M. B., & Kalyanaraman, B. (2019) · Oncotarget · doi:10.18632/oncotarget.26943 · Cited by 24
“The role of iron and ROS in cancer tumor proliferation and tumor growth and metastasis is paradoxical [22, 23].”
The important role of ferroptosis in inflammatory bowel disease
Xie, H., Cao, C., Shu, D., Liu, T., & Zhang, T. (2024) · Frontiers in Medicine · doi:10.3389/fmed.2024.1449037 · Cited by 23
“Holotransferrin further binds to the membrane protein transferrin receptor (TFRC) to form a complex that is subsequently subjected to endocytosis (26, 31).”
BackgroundResearch progress on the occurrence and therapeutic mechanism of ferroptosis in NSCLC
Zhang, Y., Guo, R., Li, J., & Zhu, L. (2021) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-021-02178-z · Cited by 21
“According to other articles, P62Keap1-NRF232 (Manz et al.”
BackgroundHuang, N. J., Wei, Y., Cheng, Y., Wang, X., Wang, Q., Chen, D., & Li, W. (2022) · Genes & Genomics · doi:10.1007/s13258-021-01205-w · Cited by 21
“Dysregulation of iron uptake and metabolism is associated with many diseases, including cancer (Forciniti et al. 2020; Manz et al. 2016; Torti and Torti 2013), kidney disease(Ganz and Nemeth 2016), cardiovascular disease(Kobayashi et al.”
Background
Metadata
- Authors
- Manz, D. H., Blanchette, N. L., Paul, B. T., Torti, F. M., & Torti, S. V.
- Affiliations
- Department of Molecular Biology and Biophysics
- UConn Health (US)
- Corresponding author
- Torti, Suzy V.
- Venue
- Annals of the New York Academy of Sciences
- Publisher
- Wiley
- Published
- 2016-02-18
- Volume
- 1368
- Issue
- 1
- Pages
- 149-161
- ISSN
- 0077-8923 (ISSN-L)
- 1749-6632
- PMC
- PMC4870095
- OpenAlex
- W2275201610
- Cited by
- 507
- References
- 121
- Citations by year
- 2026: 24 · 2025: 49 · 2024: 69 · 2023: 78 · 2022: 66 · 2021: 77 · 2020: 46 · 2019: 43 · 2018: 31 · 2017: 14 · 2016: 10
- FWCI
- 4.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annals of the New York Academy of Sciences (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- S.V.T (CA188025)
- F.M.T (CA171101)
- D.H.M. (DE021989)
- U.S. National Institutes of Health
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Keywords
- iron metabolism, cancer, ferroptosis, ferroportin, hepcidin, iron efflux, reactive oxygen species, glutathione depletion, GPX4, ferritinophagy, ferritin degradation, tumor microenvironment, epigenetic regulation, microRNA, DNA methylation, histone acetylation, cancer therapy
- MeSH terms
- Ferroportin, Animals, Humans, Iron, Neoplasms, Reactive Oxygen Species, Iron Overload, Cation Transport Proteins
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