Iron alters cell survival in a mitochondria-dependent pathway in ovarian cancer cells
Open accessAbstract
The role of iron in the development of cancer remains unclear. We previously reported that iron reduces cell survival in a Ras/mitogen-activated protein kinase (MAPK)-dependent manner in ovarian cells; however, the underlying downstream pathway leading to reduced survival was unclear. Although levels of intracellular iron, ferritin/CD71 protein and reactive oxygen species did not correlate with iron-induced cell survival changes, we identified mitochondrial damage (via TEM) and reduced expression of outer mitochondrial membrane proteins (translocase of outer membrane: TOM20 and TOM70) in cell lines sensitive to iron. Interestingly, Ru360 (an inhibitor of the mitochondrial calcium uniporter) reversed mitochondrial changes and restored cell survival in HEY ovarian carcinoma cells treated with iron. Further, cells treated with Ru360 and iron also had reduced autophagic punctae with increased lysosomal numbers, implying cross-talk between these compartments. Mitochondrial changes were dependent on activation of the Ras/MAPK pathway since treatment with a MAPK inhibitor restored expression of TOM20/TOM70 proteins. Although glutathione antioxidant levels were reduced in HEY treated with iron, extracellular glutamate levels were unaltered. Strikingly, oxalomalate (inhibitor of aconitase, involved in glutamate production) reversed iron-induced responses in a similar manner to Ru360. Collectively, our results implicate iron in modulating cell survival in a mitochondria-dependent manner in ovarian cancer cells.
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Surplus iron is needed during early steps of tumor development for enhanced survival and proliferation of transformed cells.
“This surplus of iron is needed not only both during early steps of tumor development, e.g., enhanced survival [11] and proliferation of transformed cells [12], but also during late stages to promote the metastatic cascade.”
From Iron as a central player and promising target in cancer progression (2019) · cites this paper as [11]
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Iron as a central player and promising target in cancer progression
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“, enhanced survival [11] and proliferation of transformed cells [12], but also during late stages to promote the metastatic cascade.”
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- Authors
- Bauckman, K., Haller, E., Taran, N., Rockfield, S., Ruiz-Rivera, A., & Nanjundan, M.
- Affiliations
- Moffitt Cancer Center (US)
- University of South Florida (US)
- Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL 33620, U.S.A.
- Corresponding author
- Bauckman, Kyle
- Nanjundan, Meera
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2015-02-20
- Volume
- 466
- Issue
- 2
- Pages
- 401-413
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- PMC
- PMC4338747
- OpenAlex
- W2157853803
- Cited by
- 41
- References
- 56
- Citations by year
- 2025: 2 · 2024: 4 · 2023: 3 · 2022: 2 · 2021: 8 · 2020: 4 · 2019: 4 · 2018: 6 · 2017: 6 · 2016: 1 · 2015: 1
- FWCI
- 2.03
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Biochemical Journal (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R21CA178468)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Keywords
- iron, ovarian cancer, cell survival, mitochondria, mitochondrial calcium uniporter, Ru360, Tom20, Tom70, mitochondrial outer membrane, RAS/MAPK pathway, autophagy, lysosomes, glutathione, aconitase, glutamate, oxidative stress
- MeSH terms
- Aconitate Hydratase, Quaternary Ammonium Compounds, Antineoplastic Agents, Autophagy, Calcium Channel Blockers, Carcinoma, Cell Line, Cell Survival, Enzyme Inhibitors, Female, Ferric Compounds, Glutathione, Humans, Lysosomes, Mitochondria, Neoplasm Proteins, Ovarian Neoplasms, Ovary, Calcium Channels, Reactive Oxygen Species, Oxidative Stress, MAP Kinase Signaling System, Cell Line, Tumor
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