Mistletoe lectin activates caspase-8/FLICE independently of death receptor signaling and enhances anticancer drug-induced apoptosis.
Mistletoe lectin I (ML-I) is a major active component in plant extracts of Viscum album that is increasingly used in adjuvant cancer therapy. ML-I exerts potent immunomodulating and cytotoxic effects, although its mechanism of action is largely unknown. We show that treatment of leukemic T- and B-cell lines with ML-I induced apoptosis, which required the prior activation of proteases of the caspase family. The involvement of caspases is demonstrated because (a) a peptide caspase inhibitor almost completely prevented ML-I-induced cell death and (b) proteolytic activation of caspase-8, caspase-9, and caspase-3 was observed. Because caspase-8 has been implicated as a regulator of apoptosis mediated by death receptors, we further investigated a potential receptor involvement in ML-I-induced effects. Cell death triggered by ML-I was neither attenuated in cell clones resistant to CD95 nor in cells that were rendered refractory to other death receptors by overexpressing a dominant-negative FADD mutant. In contrast, ML-I triggered a receptor-independent mitochondria-controlled apoptotic pathway because it rapidly induced the release of cytochrome c into the cytosol. Because ML-I was also observed to enhance the cytotoxic effect of chemotherapeutic drugs, these data may provide a molecular basis for clinical trials using MLs in anticancer therapy.
Bantel
H
H
Department of Internal Medicine I, Eberhard-Karls-University, Tübingen, Germany.
Engels
I H
IH
Voelter
W
W
Schulze-Osthoff
K
K
Wesselborg
S
S
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053477:Apoptotic Protease-Activating Factor 1; D029681:Arabidopsis Proteins; D020126:Brefeldin A / Q000494:pharmacology; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003574:Cytochrome c Group / Q000502:physiology; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D004792:Enzyme Precursors / Q000378:metabolism; D005047:Etoposide / Q000494:pharmacology*; D044943:Fatty Acid Desaturases / Q000235:genetics / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells / Q000187:drug effects; D015448:Leukemia, B-Cell / Q000378:metabolism / Q000473:pathology*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000378:metabolism / Q000473:pathology*; D008928:Mitochondria / Q000502:physiology; D016685:Mitomycin / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000378:metabolism*; D028321:Plant Preparations; D010940:Plant Proteins / Q000235:genetics / Q000502:physiology*; D011506:Proteins / Q000502:physiology; D054790:Ribosome Inactivating Proteins, Type 2; D014118:Toxins, Biological / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D019014:fas Receptor / Q000502:physiology*
C506592:APAF1 protein, human; D000590:Amino Acid Chloromethyl Ketones; D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D053477:Apoptotic Protease-Activating Factor 1; D029681:Arabidopsis Proteins; D015853:Cysteine Proteinase Inhibitors; D003574:Cytochrome c Group; D004792:Enzyme Precursors; D009363:Neoplasm Proteins; D028321:Plant Preparations; D010940:Plant Proteins; D011506:Proteins; D054790:Ribosome Inactivating Proteins, Type 2; D014118:Toxins, Biological; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D019014:fas Receptor; C488862:mistletoe lectin I; C009674:ribosome inactivating protein, Viscum; D020126:Brefeldin A; D016685:Mitomycin; D005047:Etoposide; D044943:Fatty Acid Desaturases; C084083:Fad7 protein, Arabidopsis; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases