Caspase-dependent chemotherapy-induced death of glioma cells requires mitochondrial cytochrome c release.
Chemotherapeutic drug-induced apoptosis of human malignant glioma cells involves the death receptor-independent activation of caspases other than caspases 3 or 8 (Glaser et al., Oncogene 18, 5044-5053, 1999). Here, we report that caspases 1, 2, 3, 7, 8, and 9 are constitutively expressed in most human malignant glioma cell lines. Cytotoxic drug-induced apoptosisinvolves delayed activation of caspases 2, 7, and 9, but not 8 and 3, and is blocked by a broad spectrum caspase inhibitor, zVAD-fmk. Cytochrome c release from mitochondria precedes caspase activation during drug-induced apoptosis and is unaffected by zVAD-fmk or ectopic expression of the viral caspase inhibitor, crm-A. In contrast, ectopic expression of BCL-X(L) prevents drug-induced cytochrome c release, caspase activation and cell death. Thus, cancer chemotherapy targets the mitochondrial, caspase-dependent death pathway in human malignant glioma cells.
Glaser
T
T
Laboratory of Molecular Neuro-Oncology, Department of Neurology, University of Tübingen, Tübingen, Germany.
Weller
M
M
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020170:Caspase 1 / Q000378:metabolism; D053143:Caspase 2; D053148:Caspase 3; D053179:Caspase 7; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D003574:Cytochrome c Group / Q000187:drug effects* / Q000378:metabolism; D004274:DNA, Recombinant; D005910:Glioma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology; D015843:Serpins / Q000235:genetics / Q000502:physiology; D013713:Teniposide / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology; D014764:Viral Proteins; D051020:bcl-X Protein
D000590:Amino Acid Chloromethyl Ketones; D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D003574:Cytochrome c Group; D004274:DNA, Recombinant; D019253:Proto-Oncogene Proteins c-bcl-2; D015843:Serpins; D014764:Viral Proteins; D051020:bcl-X Protein; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D014750:Vincristine; D013713:Teniposide; C074641:interleukin-1beta-converting enzyme inhibitor; C505407:CASP3 protein, human; C505520:CASP7 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053143:Caspase 2; D053148:Caspase 3; D053179:Caspase 7; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D020170:Caspase 1