Enhanced sensitivity to cytochrome c-induced apoptosis mediated by PHAPI in breast cancer cells
Enhanced sensitivity to cytochrome c-induced apoptosis mediated by PHAPI in breast cancer cells
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DOI：
10.1158/0008-5472.can-05-3923
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发表时间：
2006-02-15
期刊：
影响因子：
11.2
通讯作者：
Kornbluth, S
中科院分区：
文献类型：
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作者：
Schafer, ZT;Parrish, AB;Kornbluth, S
凋亡信号传导缺陷既促进肿瘤发生，又干扰化疗。通常，化疗药物刺激细胞色素c释放到细胞质中，从而激活凋亡体。尽管癌细胞可能对细胞色素c的释放有抵抗性，但许多恶性细胞在细胞色素c诱导的凋亡体激活方面也存在缺陷，这进一步促进了化疗耐药性。我们发现，与正常细胞相比，乳腺癌细胞对细胞色素c诱导的凋亡表现出异常的敏感性。这种在其他癌症中未观察到的敏感性是由于半胱天冬酶 - 9向凋亡蛋白酶激活因子1（Apaf - 1）的半胱天冬酶招募结构域的招募增强所致。半胱天冬酶激活的增强是由PHAPI介导的，PHAPI在乳腺癌中过度表达。此外，将细胞色素c微量注射到乳腺上皮细胞中会优先杀死恶性细胞，这表明这种现象可能被用于化疗目的。
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.