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PMID: 25697096 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Iron alters cell survival in a mitochondria-dependent pathway in ovarian cancer cells.

The Biochemical journal ·Vol. 466 ·No. 2 ·2015-03-01 ·Pages 401-13

Bauckman K, Haller E, Taran N, Rockfield S, Ruiz-Rivera A, Nanjundan M

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.

MeSH Terms
Aconitate Hydratase/antagonists & inhibitors,metabolism Antineoplastic Agents/chemistry,pharmacology Autophagy/drug effects Calcium Channel Blockers/pharmacology Calcium Channels/chemistry,metabolism Carcinoma/drug therapy,metabolism,ultrastructure Cell Line Cell Line, Tumor Cell Survival/drug effects Enzyme Inhibitors/pharmacology Female Ferric Compounds/antagonists & inhibitors,pharmacology Glutathione/antagonists & inhibitors,metabolism Humans Lysosomes/drug effects,metabolism,ultrastructure MAP Kinase Signaling System/drug effects Mitochondria/drug effects,metabolism,ultrastructure Neoplasm Proteins/antagonists & inhibitors,metabolism Ovarian Neoplasms/drug therapy,metabolism,ultrastructure Ovary/drug effects,metabolism,ultrastructure Oxidative Stress/drug effects Quaternary Ammonium Compounds/antagonists & inhibitors,pharmacology Reactive Oxygen Species/agonists,metabolism
Chemicals
Antineoplastic Agents Calcium Channel Blockers Calcium Channels Enzyme Inhibitors Ferric Compounds Neoplasm Proteins Quaternary Ammonium Compounds Reactive Oxygen Species mitochondrial calcium uniporter Aconitate Hydratase Glutathione ferric ammonium citrate
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Bauckman Kyle
*Cancer Biology Ph.D Program, Moffitt Cancer Center and Research Institute, Tampa, FL 33612, U.S.A.
Haller Edward
†Department of Integrative Biology, University of South Florida, Tampa, FL 33620, U.S.A.
Taran Nicholas
‡Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL 33620, U.S.A.
Rockfield Stephanie
‡Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL 33620, U.S.A.
Ruiz-Rivera Abigail
‡Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL 33620, U.S.A.
Nanjundan Meera
*Cancer Biology Ph.D Program, Moffitt Cancer Center and Research Institute, Tampa, FL 33612, U.S.A.
References (54)
54 references, click to expand
  1. Iron promotes the survival and neurite extension of serum-starved PC12 cells in the presence of NGF by enhancing cell attachment.
    Mol Cells. 2003 Feb 28;15(1):10-9 PMID: 12661755
  2. Blockade of mitochondrial calcium uniporter prevents cardiac mitochondrial dysfunction caused by iron overload.
    Acta Physiol (Oxf). 2014 Feb;210(2):330-41 PMID: 24034353
  3. Elevated levels of transferrin receptor 2 mRNA, not transferrin receptor 1 mRNA, are associated with increased survival in acute myeloid leukaemia.
    Br J Haematol. 2004 Apr;125(1):42-9 PMID: 15015967
  4. Iron metabolism and the IRE/IRP regulatory system: an update.
    Ann N Y Acad Sci. 2004 Mar;1012:1-13 PMID: 15105251
  5. Induction of ferritin expression by oxalomalate.
    Biochim Biophys Acta. 2004 May 3;1691(2-3):151-9 PMID: 15110995
  6. Cell cycle effects of iron depletion on T-47D human breast cancer cells.
    Exp Cell Res. 1985 Dec;161(2):277-84 PMID: 2998833
  7. Chemical assay of iron in ovarian cysts: a new diagnostic method to evaluate endometriotic cysts.
    Gynecol Obstet Invest. 1998;46(1):58-60 PMID: 9692345
  8. Iron alters glutamate secretion by regulating cytosolic aconitase activity.
    Am J Physiol Cell Physiol. 2005 May;288(5):C1117-24 PMID: 15613494
  9. Induction of H-ferritin synthesis by oxalomalate is regulated at both the transcriptional and post-transcriptional levels.
    Biochim Biophys Acta. 2006 Aug;1763(8):815-22 PMID: 16828896
  10. The lysosomal-mitochondrial axis theory of postmitotic aging and cell death.
    Chem Biol Interact. 2006 Oct 27;163(1-2):29-37 PMID: 16737690
  11. A proteomic analysis of the effect of MAPK pathway activation on L-glutamate-induced neuronal cell death.
    Cell Mol Biol Lett. 2007;12(1):139-47 PMID: 17124546
  12. Mitochondrial protein-import machinery: correlating structure with function.
    Trends Cell Biol. 2007 Sep;17(9):456-64 PMID: 17825565
  13. Non-transferrin-bound iron reaches mitochondria by a chelator-inaccessible mechanism: biological and clinical implications.
    Am J Physiol Cell Physiol. 2007 Oct;293(4):C1383-94 PMID: 17670894
  14. Contents of endometriotic cysts, especially the high concentration of free iron, are a possible cause of carcinogenesis in the cysts through the iron-induced persistent oxidative stress.
    Clin Cancer Res. 2008 Jan 1;14(1):32-40 PMID: 18172249
  15. Overexpression of cellular iron import proteins is associated with malignant progression of esophageal adenocarcinoma.
    Clin Cancer Res. 2008 Jan 15;14(2):379-87 PMID: 18223212
  16. Translocation of iron from lysosomes into mitochondria is a key event during oxidative stress-induced hepatocellular injury.
    Hepatology. 2008 Nov;48(5):1644-54 PMID: 18846543
  17. Advancement of the study on iron metabolism and regulation in tumor cells.
    Chin J Cancer. 2010 Apr;29(4):451-5 PMID: 20346225
  18. Mitochondrial iron trafficking and the integration of iron metabolism between the mitochondrion and cytosol.
    Proc Natl Acad Sci U S A. 2010 Jun 15;107(24):10775-82 PMID: 20495089
  19. Cytotoxic potency of H2O2 in cell cultures: impact of cell concentration and exposure time.
    Free Radic Biol Med. 2010 Nov 1;49(8):1298-305 PMID: 20673847
  20. Arsenic trioxide induces a beclin-1-independent autophagic pathway via modulation of SnoN/SkiL expression in ovarian carcinoma cells.
    Cell Death Differ. 2010 Dec;17(12):1867-81 PMID: 20508647
  21. Regulation of cellular iron metabolism.
    Biochem J. 2011 Mar 15;434(3):365-81 PMID: 21348856
  22. Advances in metal-induced oxidative stress and human disease.
    Toxicology. 2011 May 10;283(2-3):65-87 PMID: 21414382
  23. Parkin mediates proteasome-dependent protein degradation and rupture of the outer mitochondrial membrane.
    J Biol Chem. 2011 Jun 3;286(22):19630-40 PMID: 21454557
  24. Hepcidin and ferroportin: the new players in iron metabolism.
    Semin Liver Dis. 2011 Aug;31(3):272-9 PMID: 21901657
  25. Oxalomalate, a competitive inhibitor of aconitase, modulates the RNA-binding activity of iron-regulatory proteins.
    Biochem J. 2000 Jun 1;348 Pt 2:315-20 PMID: 10816424
  26. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing.
    EMBO J. 2000 Nov 1;19(21):5720-8 PMID: 11060023
  27. Functions of outer membrane receptors in mitochondrial protein import.
    Biochim Biophys Acta. 2002 Sep 2;1592(1):3-14 PMID: 12191763
  28. Free radicals, antioxidants, and nutrition.
    Nutrition. 2002 Oct;18(10):872-9 PMID: 12361782
  29. Differential effects of catalase on apoptosis induction in human promonocytic cells. Relationships with heat-shock protein expression.
    Mol Pharmacol. 2003 Mar;63(3):581-9 PMID: 12606765
  30. The role of lysosomes in iron metabolism and recycling.
    Int J Biochem Cell Biol. 2011 Dec;43(12):1686-97 PMID: 21907822
  31. Ferroptosis: an iron-dependent form of nonapoptotic cell death.
    Cell. 2012 May 25;149(5):1060-72 PMID: 22632970
  32. Mitochondrial calcium uniporter blocker prevents cardiac mitochondrial dysfunction induced by iron overload in thalassemic mice.
    Biometals. 2012 Dec;25(6):1167-75 PMID: 22910858
  33. Mitoferrin-2-dependent mitochondrial iron uptake sensitizes human head and neck squamous carcinoma cells to photodynamic therapy.
    J Biol Chem. 2013 Jan 4;288(1):677-86 PMID: 23135267
  34. Mitochondrial calcium uniporter blocker effectively prevents brain mitochondrial dysfunction caused by iron overload.
    Life Sci. 2013 Mar 12;92(4-5):298-304 PMID: 23333832
  35. Tom70 is essential for PINK1 import into mitochondria.
    PLoS One. 2013;8(3):e58435 PMID: 23472196
  36. The dual PI3K/mTOR inhibitor NVP-BEZ235 and chloroquine synergize to trigger apoptosis via mitochondrial-lysosomal cross-talk.
    Int J Cancer. 2013 Jun 1;132(11):2682-93 PMID: 23151917
  37. Iron modulates cell survival in a Ras- and MAPK-dependent manner in ovarian cells.
    Cell Death Dis. 2013;4:e592 PMID: 23598404
  38. Iron and cancer: more ore to be mined.
    Nat Rev Cancer. 2013 May;13(5):342-55 PMID: 23594855
  39. Translocation of iron from lysosomes to mitochondria during ischemia predisposes to injury after reperfusion in rat hepatocytes.
    Free Radic Biol Med. 2013 Oct;63:243-53 PMID: 23665427
  40. The TOMM machinery is a molecular switch in PINK1 and PARK2/PARKIN-dependent mitochondrial clearance.
    Autophagy. 2013 Nov 1;9(11):1801-17 PMID: 24149440
  41. The complex interplay of iron metabolism, reactive oxygen species, and reactive nitrogen species: insights into the potential of various iron therapies to induce oxidative and nitrosative stress.
    Free Radic Biol Med. 2013 Dec;65:1174-94 PMID: 24036104
  42. The role of iron and reactive oxygen species in cell death.
    Nat Chem Biol. 2014 Jan;10(1):9-17 PMID: 24346035
  43. The many faces of mitophagy.
    EMBO Rep. 2014 Jan;15(1):5-6 PMID: 24398127
  44. IRP2 regulates breast tumor growth.
    Cancer Res. 2014 Jan 15;74(2):497-507 PMID: 24285726
  45. The distinguishing cellular and molecular features of the endometriotic ovarian cyst: from pathophysiology to the potential endometrioma-mediated damage to the ovary.
    Hum Reprod Update. 2014 Mar-Apr;20(2):217-30 PMID: 24129684
  46. Iron availability is increased in individual human ovarian follicles in close proximity to an endometrioma compared with distal ones.
    Hum Reprod. 2014 Mar;29(3):577-83 PMID: 24430779
  47. Review: iron metabolism and the role of iron in neurodegenerative disorders.
    Neuropathol Appl Neurobiol. 2014 Apr;40(3):240-57 PMID: 24164678
  48. Fixing frataxin: 'ironing out' the metabolic defect in Friedreich's ataxia.
    Br J Pharmacol. 2014 Apr;171(8):2174-90 PMID: 24138602
  49. Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy.
    Nature. 2014 May 1;509(7498):105-9 PMID: 24695223
  50. Parkin and PINK1: much more than mitophagy.
    Trends Neurosci. 2014 Jun;37(6):315-24 PMID: 24735649
  51. The interplay between mitochondrial protein and iron homeostasis and its possible role in ageing.
    Exp Gerontol. 2014 Aug;56:123-34 PMID: 24394155
  52. Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis.
    Elife. 2014;3:e02523 PMID: 24844246
  53. Lysosomal membrane permeabilization in cell death: concepts and challenges.
    Mitochondrion. 2014 Nov;19 Pt A:49-57 PMID: 24984038
  54. Mitochondrial membrane permeabilization is a critical step of lysosome-initiated apoptosis induced by hydroxychloroquine.
    Oncogene. 2003 Jun 19;22(25):3927-36 PMID: 12813466
Article Info
Journal
The Biochemical journal
Abbr.
Biochem J
ISSN
1470-8728
DOI
10.1042/BJ20140878
Published
2015-03-01
Pages
401-13
Language
English
Region
England
NLM ID
2984726R
PMCID
PMC4338747
Subset
IM
Grants
NCI NIH HHS · R21 CA178468 · United States
NCI NIH HHS · R21 CA178468-01A1 · United States
External Links
PubMed source DOI: 10.1042/BJ20140878 PMC Full Text View journal details
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