Arsenic trioxide induces regulated, death receptor-independent cell death through a Bcl-2-controlled pathway.
Arsenic trioxide (As2O3, arsenite) efficiently kills cells from various hematologic malignancies and has successfully been employed especially for the treatment of acute promyelocytic leukemia. There and in lymphoid cells, we demonstrated that As2O3 induces cell death in a caspase-2- and -9-independent fashion. Here, we address a potential role of death receptor signaling through the FADD/caspase-8 death-inducing signaling complex in As2O3-induced cell death. In detail, we demonstrate that As2O3 induces cell death independently of caspase-8 or FADD and cannot be blocked by disruption of CD95/Fas receptor ligand interaction. Unlike in death receptor ligation-induced apoptosis, As2O3-induced cell death was not blocked by the broad-spectrum caspase inhibitor z-VAD-fmk or the caspase-8-specific inhibitor z-IETD-fmk. Nevertheless, As2O3-induced cell death occurred in a regulated manner and was abrogated upon Bcl-2 overexpression. In contrast, As2O3-induced cell demise was neither blocked by the caspase-9 inhibitor z-LEHD-fmk nor substantially inhibited through the expression of a dominant negative caspase-9 mutant. Altogether our data demonstrate that As2O3-induced cell death occurs independently of the extrinsic death receptor pathway of apoptosis. Cell death proceeds entirely via an intrinsic, Bcl-2-controlled mitochondrial pathway that does, however, not rely on caspase-9.
Scholz
Christian
C
Department of Hematology, Oncology and Tumor Immunology, University Medical Center Charité, Campus Buch, Humboldt University, Berlin, Germany.
Richter
Antje
A
Lehmann
Mario
M
Schulze-Osthoff
Klaus
K
Dörken
Bernd
B
Daniel
Peter T
PT
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053200:Fas-Associated Death Domain Protein; D006801:Humans; D019169:Jurkat Cells; D008024:Ligands; D008928:Mitochondria / Q000187:drug effects; D010087:Oxides / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D019014:fas Receptor / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D001152:Arsenicals; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D008024:Ligands; D010087:Oxides; D019253:Proto-Oncogene Proteins c-bcl-2; D019014:fas Receptor; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D000077237:Arsenic Trioxide