Molecular alterations in apoptotic pathways after PKB/Akt-mediated chemoresistance in NCI H460 cells.
Molecular alterations in apoptotic pathways after PKB/Akt-mediated chemoresistance in NCI H460 cells.
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DOI：
10.1038/sj.bjc.6601876
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发表时间：
2004-06-14
影响因子：
8.8
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中科院分区：
文献类型：
--
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蛋白激酶 B/Akt 被描述为癌细胞中抗凋亡信号的中心介质。此外，Akt 已被证明可以影响细胞周期进程和增殖途径，并在肿瘤发生和化疗耐药中具有潜在功能。在这项研究中，我们发现 Akt1 (CA-Akt1) 组成型活性形式的异位表达导致 NCI H460 人 NSCLC 细胞对一组化疗药物的化疗耐药性增强。为了了解激活的 Akt 介导的导致化疗敏感性受损的分子改变，我们分析了各种凋亡途径，包括 p53、半胱天冬酶 3、7、8 和 9 的激活、线粒体中细胞色素 c 的释放，以及促凋亡蛋白和抗凋亡蛋白（如 Bcl-2、Bcl-xL、Bcl-xs、Bax 或 Bfl-1）的表达水平。我们观察到 CA-Akt 的表达不会干扰单一定义的细胞凋亡开关，而是调节多个细胞凋亡途径的细胞凋亡阈值，以提高起始阈值。特别是，我们发现表达 CA-Akt 的细胞在用顺铂或米托蒽醌处理后，抗凋亡 Bcl-2 家族成员蛋白 Bcl-xl 的表达增加，并且 p53 通路的启动延迟。因此，我们的数据表明 Akt 通过干扰和延迟各种凋亡途径的发生来介导 NHI H460 细胞的化疗耐药性。在所研究的分子改变中均未观察到细胞凋亡途径的完全失活。我们的数据强化了 Akt 作为细胞存活信号和/或化疗耐药性的中心介质以及作为癌细胞化学增敏的有吸引力的靶标的作用。
Protein kinase B/Akt has been described as a central mediator of antiapoptotic signals in cancer cells. Furthermore, Akt has been shown to affect cell cycle progression and proliferative pathways and to possess a potential function in tumorigenesis and chemoresistance. In this study, we show that the ectopic expression of a constitutively active form of Akt1 (CA-Akt1) results in enhanced chemoresistance of NCI H460 human NSCLC cells towards a panel of chemotherapeutic agents. To understand the molecular alterations leading to impaired chemosensitivity mediated by activated Akt, we analysed various apoptotic pathways, including the activation of p53, caspases 3, 7, 8, and 9, release of cytochrome c from mitochondria, and the expression levels of pro- and antiapoptotic proteins such as Bcl-2, Bcl-xL, Bcl-xs, Bax, or Bfl-1. We observed that expression of CA-Akt did not interfere with single defined apoptotic switches, but modulated the apoptotic threshold of several apoptotic pathways towards increasing the threshold of onset. In particular, we found that CA-Akt-expressing cells displayed increased expression of the antiapoptotic Bcl-2 family member protein Bcl-xl, and a delayed onset of the p53 pathway after treatment with cisplatin or Mitoxantrone. Thus, our data suggest that Akt mediates chemoresistance in NHI H460 cells by interfering with and delaying the onset of various apoptotic pathways. A complete inactivation of apoptotic pathways was observed in none of the molecular alterations investigated. Our data strengthen the role of Akt as a central mediator of cell survival signals and/or chemoresistance and as an attractive target for cancer cell chemosensitisation.
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影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
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Greenberg, ME
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