Reactive oxygen species modulate Zn(2+)-induced apoptosis in cancer cells.
Some recent evidence has suggested a protective role of zinc against cancer. The mechanism by which zinc exerts this action has not been defined and, in particular, it has not been clarified whether zinc may directly act on cancer cells and the molecular mechanisms involved in this effect. In this study, we examined the in vitro effect of zinc on the apoptosis of mouse TS/A mammary adenocarcinoma cells, studying the zinc-dependent modulation of the intracellular levels of reactive oxygen species (ROS) and of p53 and Fas/Fas ligand pathways. We showed that zinc concentrations ranging from 33.7 to 75 muM Zn(2+) induced apoptosis in mammary cancer cells. The apoptosis was associated with an increased production of intracellular ROS, and of p53 and Fas/Fas ligand mRNA and protein. Zn(2+) induced a faint metallothionein response in TS/A cells in comparison with mouse lymphocytes. The treatment of tumor cells with the antioxidant N-acetylcysteine was able to prevent Zn(2+)-induced apoptosis, as well as the increase of p53 and Fas ligand protein induced by zinc. The data demonstrate that zinc exerts a direct action on mammary cancer cells inducing ROS-mediated apoptosis and that the effect may be mediated by the ROS-dependent induction of p53 and Fas/Fas ligand.
Provinciali
Mauro
M
Laboratory of Tumor Immunology, Immunology Centre, Gerontology Research Department, I.N.R.C.A., Ancona, Italy. m.provinciali@inrca.it
Donnini
Alessia
A
Argentati
Katy
K
Di Stasio
Grazia
G
Bartozzi
Beatrice
B
Bernardini
Giovanni
G
D000111:Acetylcysteine / Q000494:pharmacology; D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001426:Bacterial Proteins; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D017931:DNA Primers / Q000737:chemistry; D053222:Fas Ligand Protein; D016166:Free Radical Scavengers / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008668:Metallothionein / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013481:Superoxides / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism / Q000494:pharmacology*
D001426:Bacterial Proteins; D017931:DNA Primers; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C414536:FasR protein, Rhodococcus fascians; C505658:Fasl protein, mouse; D016166:Free Radical Scavengers; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D013481:Superoxides; D008668:Metallothionein; D015032:Zinc; D000111:Acetylcysteine