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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.”
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Li, J., Liu, J., Xu, Y., Wu, R., Chen, X., Song, X., Zeh, H. J., Kang, R., Klionsky, D. J., Wang, X., et al. (2021) · Autophagy · doi:10.1080/15548627.2021.1872241 · Cited by 246
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Iron metabolism and its contribution to cancer (Review)
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Down the Iron Path: Mitochondrial Iron Homeostasis and Beyond
Dietz, J. V., Fox, J. L., & Khalimonchuk, O. (2021) · Cells · doi:10.3390/cells10092198 · Cited by 98
Sanati, M., Afshari, A. R., Kesharwani, P., Sukhorukov, V. N., & Sahebkar, A. (2022) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.05.035 · Cited by 95
Xing, N., Du, Q., Guo, S., Xiang, G., Zhang, Y., Meng, X., Li, X., & Wang, S. (2023) · Cell Death Discovery · doi:10.1038/s41420-023-01407-z · Cited by 91
“These cancer cells need more iron during the production process, and the imbalance of iron metabolism can increase the risk of cancer and promote tumor growth [14].”
BackgroundMitochondria-mediated Ferroptosis in Diseases Therapy: From Molecular Mechanisms to Implications
Feng, F., He, S., Li, X., He, J., & Luo, L. (2023) · Aging and Disease · doi:10.14336/ad.2023.0717 · Cited by 92
“Tumors, characterized by their active metabolism, high ROS levels, and elevated iron supply, are more susceptible to ferroptosis [153, 154].”
BackgroundReczyńska-Kolman, K., Marszalek, M., Zarzycki, A., Reczyński, W., Kornaus, K., Pamuła, E., & Chrzanowski, W. (2020) · Nanomaterials · doi:10.3390/nano10061076 · Cited by 87
“The prevention of iron release from the SPIONs was of utmost importance, since iron is considered as a cofactor in cancer cell proliferation [23,40].”
BackgroundPu, F., Chen, F., Zhang, Z., Shi, D., Zhong, B., Lv, X., Tucker, A. B., Fan, J., Li, A. J., Qin, K. H., et al. (2020) · Genes & Diseases · doi:10.1016/j.gendis.2020.11.019 · Cited by 90
“This outcome suggests that cells with RAS mutations have increased iron intake and reduced iron storage capacity, and the resultant iron overload can induce ferroptosis.(48,49) Studies have shown that the use of iron chelating agents (deferramine) inhibit erastin-induced ferroptosis, and supplementation with exogenous…”
BackgroundUltrasmall iron oxide nanoparticles induced ferroptosis via Beclin1/ATG5-dependent autophagy pathway
Wen, J., Chen, H., Ren, Z., Zhang, P., Chen, J., & Jiang, S. (2021) · Nano Convergence · doi:10.1186/s40580-021-00260-z · Cited by 86
Yao, J., Chen, X., Liu, X., Li, R., Zhou, X., & Qu, Y.-Q. (2021) · Cancer Cell International · doi:10.1186/s12935-021-02027-2 · Cited by 86
Effective ferroptotic small-cell lung cancer cell death from SLC7A11 inhibition by sulforaphane
Iida, Y., Okamoto-Κatsuyama, M., Maruoka, S., Mizumura, K., Shimizu, T., Shikano, S., Hikichi, M., Takahashi, M., Tsuya, K., Okamoto, S., et al. (2020) · Oncology Letters · doi:10.3892/ol.2020.12332 · Cited by 84
“Furthermore, excess iron has been found to contribute to tumor growth (39), and previous studies have reported that cancer cells exhibited increased expression levels of transferrin receptors and iron uptake (40,41).”
Zooming in and out of ferroptosis in human disease
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Sievert, K., Lawrence, M. A., Parker, C., & Baker, P. (2020) · International Journal of Health Policy and Management · doi:10.34172/ijhpm.2020.238 · Cited by 87
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Links Between Iron and Lipids: Implications in Some Major Human Diseases
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“Cancer cells are described to be “addicted” to iron [8]; indeed, their increased proliferative capacity is negatively regulated upon cellular treatment with iron chelators [82].”
BackgroundHigh-Dose Vitamin C for Cancer Therapy
Mussa, A., Idris, R. A. M., Ahmed, N., Ahmad, S., Murtadha, A. H., Din, T. A. D. A. T., Yean, C. Y., Rahman, W. F. W. A., Lazim, N. M., Uskoković, V., et al. (2022) · Pharmaceuticals · doi:10.3390/ph15060711 · Cited by 85
“Cell respiration, DNA synthesis, the cell cycle, and epigenetics are all regulated by iron and haem-associated proteins [91,93].”
BackgroundImmunogenic cell death in cancer immunotherapy
Choi, M., Shin, J., Lee, C.-E., Chung, J.-Y., Kim, M., Yan, X., Yang, W., & Cha, J. (2023) · BMB Reports · doi:10.5483/bmbrep.2023-0024 · Cited by 79
“on iron for cell growth, a new therapeutic approach using ferroptosis for cancers resistant to conventional anticancer drugs has been proposed (75-77).”
BackgroundFunctions and Implications of Autophagy in Colon Cancer
Devenport, S. N., & Shah, Y. M. (2019) · Cells · doi:10.3390/cells8111349 · Cited by 76
“Certain cancers have shown a sensitivity to ferroptosis [64] and pharmacological induction of ferroptosis is found to reduce pancreatic and hepatic cancer cell growth [63,65].”
BackgroundFlipside of the Coin: Iron Deficiency and Colorectal Cancer
Aksan, A., Farrag, K., Aksan, S., Schroeder, O., & Stein, J. M. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.635899 · Cited by 74
Chen, Y., Deng, J., Liu, F., Dai, P., An, Y., Wang, Z., & Zhao, Y. (2019) · Advanced Healthcare Materials · doi:10.1002/adhm.201900366 · Cited by 70
Mitochondrial Iron Metabolism: The Crucial Actors in Diseases
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“Iron chelators affect the initiation, growth, proliferation, and metastasis of cancer cells by targeting different stages of disease progression, including associated iron metabolic pathways and iron-containing proteins [160,173].”
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“Page 3/15 Iron is an essential element in the basic biological processes of human body, and the metabolism disorder of which is involved with the occurrence and progression of many tumors (5, 6).”
BackgroundLelièvre, P., Sancey, L., Coll, J., Deniaud, A., & Busser, B. (2020) · Cancers · doi:10.3390/cancers12123524 · Cited by 69
“Finally, the regulation of iron homeostasis is also controlled by another mechanism: miRNAs which participate in the silencing of certain RNA and have a direct effect on the post-transcriptional regulation of the genes involved in the regulation of iron metabolism [22,23].”
BackgroundFriend or Foe? Recent Strategies to Target Myeloid Cells in Cancer
Chaib, M., Chauhan, S. C., & Makowski, L. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00351 · Cited by 65
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Wang, Y., Wang, C., Guan, X., Ma, Y., Zhang, S., Li, F., Yin, Y., Sun, Z., Chen, X., & Yin, H. (2023) · Advanced Science · doi:10.1002/advs.202303812 · Cited by 67
Appropriate Size of Fe 3 O 4 Nanoparticles for Cancer Therapy by Ferroptosis
Tian, X., Ruan, L., Zhou, S., Wu, L. H., Cao, J., Qi, X., Zhang, X., & Shen, S. (2022) · ACS Applied Bio Materials · doi:10.1021/acsabm.2c00068 · Cited by 65
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Ferroptosis is Involved in Hypoxic-ischemic Brain Damage in Neonatal Rats
Lin, W., Zhang, T., Zheng, J., Zhou, Y., Lin, Z., & Fu, X. (2022) · Neuroscience · doi:10.1016/j.neuroscience.2022.02.013 · Cited by 64
“Proteins involved in iron metabolism are critical regulators of ferroptosis mechanisms (Manz et al., 2016).”
Dang, H.-H., Ta, H. D. K., Nguyen, T. T. T., Anuraga, G., Wang, C., Lee, K., & Le, N. Q. K. (2022) · Functional & Integrative Genomics · doi:10.1007/s10142-022-00883-3 · Cited by 64
“Cancer cells are avid users of iron, and its accumulation can drive tumor initiation and maintenance (Manz et al. 2016).”
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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