Tl(I) and Tl(III) activate both mitochondrial and extrinsic pathways of apoptosis in rat pheochromocytoma (PC12) cells.
Thallium (Tl) is a highly toxic metal though yet its mechanisms are poorly understood. Previously, we demonstrated that rat pheochromocytoma (PC12) cells exposure to thallous (Tl(I)) or thallic (Tl(III)) cations leads to mitochondrial damage and reduced cell viability. In the present work we comparatively characterized the possible pathways involved in Tl(I)- and Tl(III)- (10-100 muM) mediated decrease in PC12 cells viability. We observed that these cations do not cause cell necrosis but significantly increased the number of cells with apoptotic features. Both cations lead to Bax oligomerization and caused apoptosis inducing factor (AIF), endonuclease G (Endo G), and cytochrome c release from mitochondria, but they did not activate caspase dependent DNAse (CAD). Tl(I)- and Tl(III)-dependent caspases 9 and 3 activation followed similar kinetics, with maximal effects at 18 h of incubation. In addition, Tl(I) promoted phosphatidylserine (PS) exposure. Tl(III) induced 2- and 18-fold increase in Fas content and caspase 8 activity, respectively. Together, experimental results show that Tl(I) and Tl(III) induce PC12 cells apoptosis, although differential pathways are involved. While Tl(I)-mediated cell apoptosis was mainly associated with mitochondrial damage, Tl(III) showed a mixed effect triggering both the intrinsic and extrinsic pathways of apoptosis. These findings contribute to a better understanding of the mechanisms underlying Tl-induced loss of cell viability in PC12 cells.
Department of Biological Chemistry, IIMHNO (UBA) and IQUIFIB (UBA-CONICET), School of Pharmacy and Biochemistry, University of Buenos Aires, Argentina.
Cecilia Eliana
CE
Hanzel
Sandra Viviana
SV
Verstraeten
D000310:Adrenal Gland Neoplasms / Q000201:enzymology / Q000473:pathology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D003851:Deoxyribonucleases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004706:Endodeoxyribonucleases / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D009336:Necrosis; D016716:PC12 Cells; D010673:Pheochromocytoma / Q000201:enzymology / Q000473:pathology*; D010718:Phosphatidylserines / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D013793:Thallium / Q000633:toxicity*; D013997:Time Factors; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
C494831:Aifm1 protein, rat; D051033:Apoptosis Inducing Factor; C494828:Bax protein, rat; D010718:Phosphatidylserines; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; D045304:Cytochromes c; D013793:Thallium; D011065:Poly(ADP-ribose) Polymerases; D003851:Deoxyribonucleases; D004706:Endodeoxyribonucleases; C109663:caspase-activated deoxyribonuclease; C052391:endonuclease G; C505410:Casp3 protein, rat; C506435:Casp9 protein, rat; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; C042172:thallium nitrate