Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Aconitate Hydratase / antagonists & inhibitors
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Aconitate Hydratase / metabolism
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Autophagy / drug effects
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Calcium Channel Blockers / pharmacology
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Calcium Channels / chemistry
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Calcium Channels / metabolism
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Carcinoma / drug therapy*
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Carcinoma / metabolism
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Carcinoma / ultrastructure
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Cell Line
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Cell Line, Tumor
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Cell Survival / drug effects
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Enzyme Inhibitors / pharmacology
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Female
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Ferric Compounds / antagonists & inhibitors
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Ferric Compounds / pharmacology*
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Glutathione / antagonists & inhibitors
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Glutathione / metabolism
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Humans
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Lysosomes / drug effects
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Lysosomes / metabolism
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Lysosomes / ultrastructure
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MAP Kinase Signaling System / drug effects
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Mitochondria / drug effects*
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Mitochondria / metabolism
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Mitochondria / ultrastructure
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / metabolism
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Ovarian Neoplasms / drug therapy*
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Ovarian Neoplasms / metabolism
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Ovarian Neoplasms / ultrastructure
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Ovary / drug effects*
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Ovary / metabolism
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Ovary / ultrastructure
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Oxidative Stress / drug effects*
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Quaternary Ammonium Compounds / antagonists & inhibitors
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Quaternary Ammonium Compounds / pharmacology*
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Reactive Oxygen Species / agonists
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Reactive Oxygen Species / metabolism
Substances
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Antineoplastic Agents
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Calcium Channel Blockers
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Calcium Channels
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Enzyme Inhibitors
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Ferric Compounds
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Neoplasm Proteins
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Quaternary Ammonium Compounds
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Reactive Oxygen Species
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mitochondrial calcium uniporter
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Aconitate Hydratase
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Glutathione
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ferric ammonium citrate