Increased susceptibility of copper-deficient neuroblastoma cells to oxidative stress-mediated apoptosis.
Treatment of neuroblastoma cells with the copper chelator triethylene tetramine tetrahydrochloride induced intracellular decrease of copper content paralleled by diminished activity of the enzymes Cu, Zn superoxide dismutase, and cytochrome c oxidase. This effect appears to be specific for copper-enzymes and the treatment affects neither viability nor growth capability of cells. However, molecular markers of apoptosis Bcl-2, p53, and caspase-3 were slightly affected in these cells. When copper-deficient cells were challenged with oxidative stress generated by paraquat or puromycin, they underwent a higher degree of apoptosis with respect to copper-adequate control cells. The mechanism underlying paraquat-triggered apoptosis implies dramatic activation of caspase-3 and induction of the transcription factor p53. These results demonstrate that impairment of copper balance predisposes neuronal cells to apoptosis induced by oxidative stress. Overall findings represent a contribution to the comprehension of the link between copper-imbalance and neurodegeneration, which has recently been repeatedly suggested for the most invalidating pathologies of the central nervous system.
Rossi
L
L
Department of Biology, University of Rome Tor Vergata, Rome, Italy. luisa.rossi@uniroma2.it
Marchese
E
E
Lombardo
M F
MF
Rotilio
G
G
Ciriolo
M R
MR
D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology; D003300:Copper / Q000172:deficiency* / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D009447:Neuroblastoma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects; D010269:Paraquat / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011691:Puromycin / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000378:metabolism; D014266:Trientine / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D002614:Chelating Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D011691:Puromycin; D003300:Copper; D013482:Superoxide Dismutase; D003576:Electron Transport Complex IV; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D005978:Glutathione; D010269:Paraquat; D014266:Trientine