Synergy between phosphatidylinositol 3-kinase/Akt pathway and Bcl-xL in the control of apoptosis in adenocarcinoma cells of the lung.
Synergy between phosphatidylinositol 3-kinase/Akt pathway and Bcl-xL in the control of apoptosis in adenocarcinoma cells of the lung.
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DOI：
10.1158/1535-7163.mct-08-0973
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发表时间：
2009-01
影响因子：
5.7
通讯作者：
Massion PP
中科院分区：
文献类型：
--
作者：
Qian J;Zou Y;Rahman JS;Lu B;Massion PP
肺腺癌通常表现出磷脂酰肌醇3-激酶（PI 3 K）/Akt信号通路活性的增加，但许多对由PI 3 K抑制诱导的细胞凋亡具有抗性。我们假设Bcl-xL对肺腺癌中由PI 3 K/Akt通路抑制诱导的凋亡反应具有协同作用。为了测试这一点，我们检查了PI 3 K抑制剂和LY 294002对表达不同水平Bcl-xL的肺腺癌细胞系的作用。我们发现过表达Bcl-xL的细胞对LY 294002诱导的凋亡有抗性，而表达很少的Bcl-xL的细胞则没有。在表达低水平Bcl-xL的细胞中恢复Bcl-xL表达赋予响应于LY 294002的凋亡抗性。LY 294002或Akt 1 siRNA对PI 3 K/Akt通路的抑制以及ABT-737或Bcl-xL siRNA对Bcl-xL功能的同时抑制大大增强了凋亡反应。此外，这种反应与诱导促凋亡BH 3-only BCL 2家族成员Bim相关。我们的数据表明，PI 3 K/Akt和Bcl-xL途径控制细胞死亡在肺腺癌细胞中的协同方式。调节Bcl-xL的表达可能代表了一种重要的策略，以优化肺腺癌中靶向PI 3 K/Akt通路的治疗剂的功效。
Adenocarcinomas of the lung commonly show an increase in the activity of phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, yet many are resistant to apoptosis induced by the inhibition of PI3K. We hypothesized that Bcl-xL would have a synergistic effect on the apoptotic response induced by inhibition of the PI3K/Akt pathway in lung adenocarcinoma. To test this, we examined the effect of the PI3K inhibitor and LY294002 on lung adenocarcinoma cell lines expressing varying levels of Bcl-xL. We found that cells that overexpress Bcl-xL are resistant LY294002-induced apoptosis, while cells that express little Bcl-xL readily are not. Restoring Bcl-xL expression in cells that express low level of Bcl-xL conferred resistance to apoptosis in response to LY294002. The simultaneous inhibition of the PI3K/Akt pathway by LY294002 or Akt1 siRNA and Bcl-xL function by ABT-737 or Bcl-xL siRNA greatly enhanced the apoptotic response. Moreover, this response was associated with the induction of proapoptotic BH3-only BCL2 family member Bim. Our data suggest that PI3K/Akt and Bcl-xL pathways control cell death in lung adenocarcinoma cells in a synergistic manner. Modulation of Bcl-xL expression may represent one important strategy to optimize the efficacy of therapeutic agents targeting the PI3K/Akt pathway in adenocarcinoma of the lung.