Transferrin ensures survival of ovarian carcinoma cells when apoptosis is induced by TNFalpha, FasL, TRAIL, or Myc.
The activation of Myc induces apoptosis of human ovarian adenocarcinoma N.1 cells when serum factors are limited. However, the downstream mechanism that is triggered by Myc is unknown. Myc-activation and treatment with the proapoptotic ligands TNFalpha, FasL, and TRAIL induced H-ferritin expression under serum-deprived conditions. H-ferritin chelates intracellular iron and also intracellular iron sequestration by deferoxamine-induced apoptosis of N.1 cells. Supplementation of serum-free medium with holo-transferrin blocked apoptosis of N.1 cells that was induced by Myc-activation or by treatment with TNFalpha, FasL, and TRAIL, whereas apotransferrin did not prevent apoptosis. This suggests that intracellular iron depletion was a trigger for apoptosis and that transferrin-bound iron rescued N.1 cells. Furthermore, apoptosis of primary human ovarian carcinoma cells, which was induced by TNFalpha, FasL, and TRAIL, was also inhibited by holo-transferrin. The data suggest that Myc-activation, FasL, TNFalpha, and TRAIL disturbed cellular iron homeostasis, which triggered apoptosis of ovarian carcinoma cells and that transferrin iron ensured survival by re-establishing this homeostasis.
Fassl
Sandra
S
Institute of Clinical Pathology, University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
Leisser
Christina
C
Huettenbrenner
Simone
S
Maier
Susanne
S
Rosenberger
Georg
G
Strasser
Stephan
S
Grusch
Michael
M
Fuhrmann
Gerhard
G
Leuhuber
Katharina
K
Polgar
Doris
D
Stani
Josefine
J
Tichy
Brigitte
B
Nowotny
Christine
C
Krupitza
Georg
G
D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D002470:Cell Survival / Q000502:physiology*; D053222:Fas Ligand Protein; D005260:Female; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014168:Transferrin / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D016271:Proto-Oncogene Proteins c-myc; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014168:Transferrin; D014409:Tumor Necrosis Factor-alpha