Enhanced sensitivity to cytochrome c-induced apoptosis mediated by PHAPI in breast cancer cells.
Apoptotic signaling defects both promote tumorigenesis and confound chemotherapy. Typically, chemotherapeutics stimulate cytochrome c release to the cytoplasm, thereby activating the apoptosome. Although cancer cells can be refractory to cytochrome c release, many malignant cells also exhibit defects in cytochrome c-induced apoptosome activation, further promoting chemotherapeutic resistance. We have found that breast cancer cells display an unusual sensitivity to cytochrome c-induced apoptosis when compared with their normal counterparts. This sensitivity, not observed in other cancers, resulted from enhanced recruitment of caspase-9 to the Apaf-1 caspase recruitment domain. Augmented caspase activation was mediated by PHAPI, which is overexpressed in breast cancers. Furthermore, cytochrome c microinjection into mammary epithelial cells preferentially killed malignant cells, suggesting that this phenomenon might be exploited for chemotherapeutic purposes.
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Zachary T
ZT
Schafer
Amanda B
AB
Parrish
Kevin M
KM
Wright
Seth S
SS
Margolis
Jeffrey R
JR
Marks
Mohanish
M
Deshmukh
Sally
S
Kornbluth
D017209:Apoptosis / Q000187:drug effects; D053477:Apoptotic Protease-Activating Factor 1; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism / Q000494:pharmacology*; D003600:Cytosol / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D009687:Nuclear Proteins; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism*; D016601:RNA-Binding Proteins
C087425:ANP32A protein, human; C506592:APAF1 protein, human; D053477:Apoptotic Protease-Activating Factor 1; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D011506:Proteins; D016601:RNA-Binding Proteins; D045304:Cytochromes c; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases