Smac is required for cytochrome c-induced apoptosis in prostate cancer LNCaP cells.
Release of cytochrome c from mitochondria to cytosol has been identified as one of the central events of apoptosis. Direct injection of cytochrome c induces apoptosis in some but not in all cell types. We observed that LNCaP prostate cancer cells failed to undergo apoptosis induced by cytochrome c microinjections. Microinjection of cytochrome c with another mitochondrial protein, Smac, was sufficient to activate caspases, however. Smac is believed to function as a neutralizer of caspase inhibitors, and mass spectrometry analysis identified XIAP as a predominant Smac binding protein in LNCaP cells. These findings are consistent with a requirement for a release of Smac from mitochondria to enable caspase activation in prostate cells. Indeed, translocation of Smac from mitochondria to cytosol was observed in LNCaP cells that undergo apoptosis and was inhibited by epidermal growth factor, which is a survival factor for these cells. These results further emphasize the central role of mitochondria in the regulation of apoptosis in prostate cancer cells.
Carson
Jonathan P
JP
Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908, USA.
Behnam
Marcelina
M
Sutton
Jennifer N
JN
Du
Chunying
C
Wang
Xiaodong
X
Hunt
Donald F
DF
Weber
Michael J
MJ
Kulik
George
G
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000008:administration & dosage* / Q000378:metabolism; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D003574:Cytochrome c Group / Q000008:administration & dosage*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006736:Horses; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D008845:Microinjections; D024101:Mitochondrial Proteins / Q000008:administration & dosage* / Q000378:metabolism; D008969:Molecular Sequence Data; D009025:Morpholines / Q000494:pharmacology; D011233:Precipitin Tests; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000378:metabolism; D014407:Tumor Cells, Cultured; D051636:X-Linked Inhibitor of Apoptosis Protein
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D002867:Chromones; D003574:Cytochrome c Group; C412403:DIABLO protein, human; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D024101:Mitochondrial Proteins; D009025:Morpholines; D011506:Proteins; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases