Dieldrin promotes proteolytic cleavage of poly(ADP-ribose) polymerase and apoptosis in dopaminergic cells: protective effect of mitochondrial anti-apoptotic protein Bcl-2.
Previously, we demonstrated that the organochlorine pesticide dieldrin induces mitochondrial depolarization, caspase-3 activation and apoptosis in dopaminergic PC12 cells. We also demonstrated that protein kinase Cdelta (PKCdelta), a member of a novel PKC family of proteins, is proteolytically activated by caspase-3 to mediate apoptotic cell death processes. In the present study, we have further characterized the protective effect of the major mitochondrial anti-apoptotic protein Bcl-2 against dieldrin-induced apoptotic events in dopaminergic cells. Exposure to dieldrin (30-100 microM) produced significant cytotoxicity and caspase-3 activation within 3h in vector-transfected PC12 cells, whereas human Bcl-2-transfected PC12 cells were almost completely resistant to dieldrin-induced cytotoxicity and caspase-3 activation. Also, dieldrin (30-300 microM) treatment induced proteolytic cleavage of poly(ADP-ribose) polymerase (PARP), which was blocked by pretreatment with caspase-3 inhibitors Z-DEVD-FMK and Z-VAD-FMK. Additionally, dieldrin-induced chromatin condensation and DNA fragmentation were completely blocked in Bcl-2-overexpressed PC12 cells as compared to vector control cells. Together, these results clearly indicate that overexpression of mitochondrial anti-apoptotic protein protects against dieldrin-induced apoptotic cell death and further suggest that dieldrin primarily alters mitochondrial function to initiate apoptotic cell death in dopaminergic cells.
Kitazawa
Masashi
M
Parkinson's Disorder Research Laboratory, Department of Biomedical Sciences, Iowa State University, 2062 Veterinary Medicine Building, Ames, IA 50011-1250 USA.
Anantharam
Vellareddy
V
Kanthasamy
Arthi
A
Kanthasamy
Anumantha G
AG
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D053938:DNA Fragmentation / Q000187:drug effects / Q000502:physiology; D004026:Dieldrin / Q000037:antagonists & inhibitors / Q000633:toxicity*; D004298:Dopamine / Q000502:physiology*; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology*; D016716:PC12 Cells; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000502:physiology*; D051381:Rats
D019253:Proto-Oncogene Proteins c-bcl-2; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D004026:Dieldrin; D004298:Dopamine