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Enhanced Sensitivity to Cytochrome c–Induced Apoptosis Mediated by PHAPI in Breast Cancer Cells

Departments of ¹ Pharmacology and Cancer Biology and ² Surgery, Duke University Medical Center; ³ Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina; and ⁴ Neuroscience Center, University of North Carolina, Chapel Hill, North Carolina

Requests for reprints: Sally Kornbluth, Department of Pharmacology and Cancer Biology, Duke University Medical Center, Box 3813, Durham, NC 27710. Phone: 919-613-8624; Fax: 919-681-1005; E-mail: kornb001{at}mc.duke.edu.

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. (Cancer Res 2006; 66(4): 2210-8)

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