Doxorubicin-induced apoptosis in human T-cell leukemia is mediated by caspase-3 activation in a Fas-independent way.
It has recently been proposed that doxorubicin (DOX) can induce apoptosis in human T-leukemia cells via the Fas/FasL system in an autocrine/paracrine way. We show here that treatment of Jurkat cells with either anti-Fas antibodies, anthracyclin drugs or actinomycin D induces the activation of CPP32 (caspase-3) and apoptosis. However, DOX treatment did not induce the expression of membrane FasL or the release of soluble FasL and co-incubation with blocking anti-Fas antibodies prevented Fas-induced but not DOX-induced apoptosis. All the morphological and biochemical signs of apoptosis induced by anti-Fas or DOX can be prevented by Z-VAD-fmk, a general caspase inhibitor. DEVD-cho, a specific inhibitor of CPP32-like caspases which completely blocks Fas-mediated apoptosis, prevented drug-induced nuclear apoptosis but not cell death. We conclude that: (i) DOX-induced apoptosis in human T-leukemia/lymphoma is Fas-independent and (ii) caspase-3 is responsible of DOX-induced nuclear apoptosis but other Z-VAD-sensitive caspases are implicated in cell death.
Gamen
S
S
Departamento de Bioquímica y Biologia Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Spain.
Anel
A
A
Lasierra
P
P
Alava
M A
MA
Martinez-Lorenzo
M J
MJ
Piñeiro
A
A
Naval
J
J
D017304:Annexin A5 / Q000502:physiology; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000096:biosynthesis / Q000378:metabolism*; D003609:Dactinomycin / Q000494:pharmacology; D004317:Doxorubicin / Q000633:toxicity*; D004789:Enzyme Activation; D004790:Enzyme Induction; D004792:Enzyme Precursors / Q000378:metabolism; D053222:Fas Ligand Protein; D006801:Humans; D019169:Jurkat Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D016399:Lymphoma, T-Cell; D008562:Membrane Glycoproteins / Q000276:immunology / Q000502:physiology; D008727:Methotrexate / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology; D019014:fas Receptor / Q000502:physiology
D017304:Annexin A5; D000906:Antibodies; D004792:Enzyme Precursors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019014:fas Receptor; D003609:Dactinomycin; D014750:Vincristine; D004317:Doxorubicin; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases; D008727:Methotrexate