Constitutive presence of cytochrome c in the cytosol of a chemoresistant leukemic cell line.
The release of holocytochrome c (cyt c) from mitochondria into the cytosol is reportedly a landmark of the execution phase of apoptosis. As shown here, the P-glycoprotein- (P-gp) expressing K562/ADR cell line (but not the parental K562 cell line) exhibits both cytosolic and mitochondrial cyt c in the absence of any signs of apoptosis. K562/ADR cells were found to be relatively resistant to a variety of different inducers of apoptosis, and blocking the P-gp did not reverse this resistance. The release of cyt c in non-apoptotic K562/ADR cells was not accompanied by that of any other mitochondrial apoptogenic protein, such as AIF or Smac/DIABLO, and was inhibited by Bcl-2 over expression. In addition, using a cell-free system, we show that mitochondria isolated from K562/ADR cells spontaneously released cyt c. These data suggest that cyt c release may be compatible with the preservation of mitochondrial integrity and function, as well as cell proliferation.
Oliver
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Equipe 4, UMR 601 INSERM/Université de Nantes, 9 Quai Moncousu, 44035 Nantes Cedex 01, France.
LeCabellec
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MT
Pradal
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Meflah
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Kroemer
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Vallette
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D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D045304:Cytochromes c / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D020014:K562 Cells; D007938:Leukemia / Q000378:metabolism*; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D016133:Polymerase Chain Reaction; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D045304:Cytochromes c