Inactivation of the apoptosis effector Apaf-1 in malignant melanoma
Inactivation of the apoptosis effector Apaf-1 in malignant melanoma
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DOI：
10.1038/35051606
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发表时间：
2001-01-11
期刊：
影响因子：
64.8
通讯作者：
Lowe, SW
中科院分区：
文献类型：
--
作者：
Soengas, MS;Capodieci, P;Lowe, SW
转移性黑色素瘤是一种致命的癌症，对常规化疗无效，在分子水平上了解很少(1)。P53突变经常发生在侵袭性癌症和化疗耐药癌症中，但很少在黑色素瘤中观察到(1，2)。在这里，我们显示转移性黑色素瘤通常失去APAF-1，这是一种细胞死亡效应因子，与细胞色素c和caspase-9共同作用，介导依赖于p53的细胞凋亡(3)。在转移性黑色素瘤中，APAF-1的表达缺失伴随着等位基因缺失，但在黑色素瘤细胞系中，可以通过甲基化抑制剂5-氮杂-2‘-脱氧胞苷(5aza2dC)的治疗而恢复。APAF-1阴性的黑色素瘤总是耐药的，不能执行典型的凋亡程序来响应P53的激活。通过基因转移或5aza2dC治疗恢复APAF-1的生理水平可显著增强化疗敏感性，挽救与APAF-1缺失相关的细胞凋亡缺陷。我们得出结论，APAF-1在转移性黑色素瘤中失活，导致细胞在执行凋亡死亡过程中存在缺陷。APAF-1缺失可能是在这种高度耐药的肿瘤类型中观察到的P53突变频率较低的原因。
Metastatic melanoma is a deadly cancer that fails to respond to conventional chemotherapy and is poorly understood at the molecular level(1). p53 mutations often occur in aggressive and chemoresistant cancers but are rarely observed in melanoma(1,2). Here we show that metastatic melanomas often lose Apaf-1, a cell-death effector that acts with cytochrome c and caspase-9 to mediate p53-dependent apoptosis(3). Loss of Apaf-1 expression is accompanied by allelic loss in metastatic melanomas, but can be recovered in melanoma cell lines by treatment with the methylation inhibitor 5-aza-2'-deoxycytidine (5aza2dC). Apaf-1-negative melanomas are invariably chemoresistant and are unable to execute a typical apoptotic programme in response to p53 activation. Restoring physiological levels of Apaf-1 through gene transfer or 5aza2dC treatment markedly enhances chemosensitivity and rescues the apoptotic defects associated with Apaf-1 loss. We conclude that Apaf-1 is inactivated in metastatic melanomas, which leads to defects in the execution of apoptotic cell death. Apaf-1 loss may contribute to the low frequency of p53 mutations observed in this highly chemoresistant tumour type.