Histone deacetylase inhibitors induced caspase-independent apoptosis in human pancreatic adenocarcinoma cell lines
Histone deacetylase inhibitors induced caspase-independent apoptosis in human pancreatic adenocarcinoma cell lines
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DOI：
10.1158/1535-7163.mct-04-0186
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发表时间：
2005-08-01
影响因子：
5.7
通讯作者：
Saceda, M
中科院分区：
文献类型：
--
作者：
García-Morales, P;Gómez-Martínez, A;Saceda, M
在三种充分表征的胰腺癌细胞系IMIM-PC-1、IMIM-PC-2和RWP-1中测试组蛋白脱乙酰酶抑制剂的抗肿瘤活性。这些细胞系先前已根据其来源、这种肿瘤的相关分子标记物的状态、对其他化疗药物的抗性以及分化标记物的表达来表征。在这项研究中，我们报告了组蛋白去乙酰化酶抑制剂诱导胰腺癌细胞系凋亡，独立于其对常规化疗药物的内在抗性。组蛋白去乙酰化酶抑制剂诱导的细胞凋亡是由于丝氨酸蛋白酶依赖和半胱天冬酶非依赖的机制。最初，组蛋白去乙酰化酶抑制剂增加Bax蛋白水平而不影响Bcl-2水平。因此，凋亡诱导因子（AIF）和Omi/HtrA 2从线粒体释放，随后诱导凋亡程序。这些现象需要AIF重新定位到细胞核中以诱导DNA片段化和Omi/HtrA 2的丝氨酸蛋白酶活性。这些数据，连同以前的结果，从其他细胞模型轴承的多药耐药表型，组蛋白去乙酰化酶抑制剂作为治疗人胰腺癌的抗肿瘤药物的可能作用。
The antitumor activity of the histone deacetylase inhibitors was tested in three well-characterized pancreatic adenocarcinoma cell lines, IMIM-PC-1, IMIM-PC-2, and RWP-1. These cell lines have been previously characterized in terms of their origin, the status of relevant molecular markers for this kind of tumor, resistance to other antineoplastic drugs, and expression of differentiation markers. In this study, we report that histone deacetylase inhibitors induce apoptosis in pancreatic cancer cell lines, independently of their intrinsic resistance to conventional antineoplastic agents. The histone deacetylase inhibitor induced apoptosis is due to a serine protease-dependent and caspase-independent mechanism. Initially, histone deacetylase inhibitors increase Bax protein levels without affecting Bcl-2 levels. Consequently, the apoptosis-inducing factor (AIF) and Omi/HtrA2 are released from the mitochondria, with the subsequent induction of the apoptotic program. These phenomena require AIF relocalization into the nuclei to induce DNA fragmentation and a serine protease activity of Omi/HtrA2. These data, together with previous results from other cellular models bearing the multidrug resistance phenotype, suggest a possible role of the histone deacetylase inhibitors as antineoplastic agents for the treatment of human pancreatic adenocarcinoma.