AKT1, AKT2 and AKT3-dependent cell survival is cell line-specific and knockdown of all three isoforms selectively induces apoptosis in 20 human tumor cell lines
AKT1, AKT2 and AKT3-dependent cell survival is cell line-specific and knockdown of all three isoforms selectively induces apoptosis in 20 human tumor cell lines
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DOI：
10.4161/cbt.6.5.3995
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发表时间：
2007-05-01
影响因子：
3.6
通讯作者：
Zou, Jun
中科院分区：
文献类型：
--
作者：
Koseoglu, Sandra;Lu, Zhuomei;Zou, Jun
AKT是PTEN/PI 3 K/AKT途径中的关键丝氨酸/苏氨酸激酶（1），并且AKT的活化经常在人类癌症中观察到。为了探索AKT在不同肿瘤细胞中的细胞存活中的作用，我们测试了20种人类肿瘤细胞系对通过小干扰RNA（siRNA）和/或激酶死亡突变体AKT敲低AKT的响应。siRNA介导的肿瘤细胞系中所有三种AKT亚型的敲低导致AKT底物磷酸化的减少。敲低AKT导致11个AKT激活的肿瘤细胞中有6个发生凋亡。与此相反，敲低AKT诱导细胞凋亡的9个细胞系中的3个具有低水平的活性AKT。细胞对敲低AKT的反应性不受p53突变状态的影响，但似乎与HER 2过表达相关。为了评估单个AKT同种型的作用，进一步表征了对AKT敲低有响应的五种细胞系。在ZR-75细胞中，AKT 1是负责细胞增殖和存活的主要同种型。相反，在IGROV 1细胞中，AKT 2在细胞增殖中起主要作用，但没有单一亚型对细胞存活至关重要。因此，AKT同种型的相对重要性是细胞系特异性的。我们的数据表明，抑制所有三种AKT亚型是必要的，以引起最大的肿瘤细胞凋亡反应，激活AKT的水平是一个有利的，但并不总是可靠的生物标志物，用于预选的响应肿瘤细胞系AKT抑制剂。
AKT is a key serine/threonine kinase in the PTEN/PI3K/AKT pathway(1) and activation of AKT is often observed in human cancers. To explore the role of AKT in cell survival in different tumor cells, we tested 20 human tumor cell lines for response to knockdown of AKT by small interference RNA (siRNA) and/or a kinase-dead mutant AKT. siRNA-mediated knockdown of all three AKT isoforms in tumor cell lines led to a reduction of phosphorylation of AKT substrates. Knockdown of AKT resulted in apoptosis in 6 out of 11 tumor cells with activated AKT. In contrast, knockdown of AKT induced apoptosis in three out of nine cell lines with a low level of active AKT. The responsiveness of the cells to knockdown of AKT was not affected by mutational status of p53 but appeared correlated with overexpression of HER2. To assess the role of individual AKT isoforms, five of the cell lines responsive to knockdown of AKT were further characterized. In ZR-75 cells, AKT1 is the predominant isoform responsible for cell proliferation and survival. Conversely, in IGROV1 cells, AKT2 plays a major role in cell proliferation, but no single isoform is essential for cell survival. Thus, the relative importance of the AKT isoforms is cell line-specific. Our data suggest that inhibiting all three AKT isoforms is necessary to elicit maximal apoptotic response in tumor cells, and the level of activated AKT is a favorable but not always reliable biomarker for preselection of responsive tumor cell lines to AKT inhibitors.