Rapid extracellular release of cytochrome c is specific for apoptosis and marks cell death in vivo.
Diverse death stimuli including anticancer drugs trigger apoptosis by inducing the translocation of cytochrome c from the outer mitochondrial compartment into the cytosol. Once released, cytochrome c cooperates with apoptotic protease-activating factor-1 and deoxyadenosine triphosphate in caspase-9 activation and initiation of the apoptotic protease cascade. The results of this study show that on death induction by chemotherapeutic drugs, staurosporine and triggering of the death receptor CD95, cytochrome c not only translocates into the cytosol, but furthermore can be abundantly detected in the extracellular medium. The cytochrome c release from the cell is a rapid and apoptosis-specific process that occurred within 1 hour after induction of apoptosis, but not during necrosis. Interestingly, elevated cytochrome c levels were observed in sera from patients with hematologic malignancies. In the course of cancer chemotherapy, the serum levels of cytochrome c in the majority of the patients grew rapidly as a result of increased cell death. These data suggest that monitoring of cytochrome c in the serum of patients with tumors might serve as a useful clinical marker for the detection of the onset of apoptosis and cell turnover in vivo.
Renz
A
A
Department of Immunology and Cell Biology, University of Münster, D-48149 Münster, Germany.
Berdel
W E
WE
Kreuter
M
M
Belka
C
C
Schulze-Osthoff
K
K
Los
M
M
D000328:Adult; D000368:Aged; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015415:Biomarkers; D014408:Biomarkers, Tumor; D002642:Chick Embryo; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003574:Cytochrome c Group / Q000097:blood / Q000378:metabolism*; D003600:Cytosol / Q000201:enzymology; D003609:Dactinomycin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000201:enzymology; D005260:Female; D019337:Hematologic Neoplasms / Q000201:enzymology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D019169:Jurkat Cells / Q000187:drug effects / Q000201:enzymology; D007739:L Cells / Q000187:drug effects / Q000201:enzymology; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008297:Male; D051379:Mice; D008875:Middle Aged; D008928:Mitochondria / Q000201:enzymology*; D009336:Necrosis; D009363:Neoplasm Proteins / Q000097:blood; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D021381:Protein Transport; D019311:Staurosporine / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000590:Amino Acid Chloromethyl Ketones; D015415:Biomarkers; D014408:Biomarkers, Tumor; D015853:Cysteine Proteinase Inhibitors; D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D014409:Tumor Necrosis Factor-alpha; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D003609:Dactinomycin; D006861:Hydrogen Peroxide; D007770:L-Lactate Dehydrogenase; D019311:Staurosporine