Selective protection by hsp 70 against cytotoxic drug-, but not Fas-induced T-cell apoptosis.
The phenomenon of heat-shock (HS) protection to many cytotoxic insults has previously been described; however, the specific molecular mechanism underlying this HS-mediated protection remains undefined. To gain insight into this protective mechanism, heat-shocked Jurkat T cells were treated with a range of cytotoxic agents. Those against which HS conferred protection (camptothecin and actinomycin D) were compared with agents against which HS showed no protective effect (anti-Fas monoclonal antibody (mAb)). Reactive oxygen species (ROS) production was found to be an event common to apoptosis induced by camptothecin and actinomycin D, whereas Fas-mediated apoptosis was shown to occur via a ROS-independent mechanism. The selective protection observed against these agents was found to be mimicked by pretreatment with antioxidant compounds. Furthermore, this antioxidant protection appears to be occurring downstream of ROS production. Experiments were extended using heat-shock protein (hsp) 70 gene-transfected Jurkat T cells to confirm that the protective effects observed were caused by hsp 70 synthesis rather than any other cellular response to HS. Bcl-2 expression levels were also examined to determine whether any correlation existed between Bcl-2- and hsp 70-mediated protection.
Creagh
E M
EM
Tumour Biology Laboratory, Department of Biochemistry, University College Cork, Cork, Ireland.
Cotter
T G
TG
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D015153:Blotting, Western; D002166:Camptothecin / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D018869:Heat-Shock Response / Q000276:immunology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D019169:Jurkat Cells; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D019014:fas Receptor / Q000276:immunology*
D000970:Antineoplastic Agents; D000975:Antioxidants; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D019014:fas Receptor; D003609:Dactinomycin; D006861:Hydrogen Peroxide; D002166:Camptothecin