Blockage of Stat3 enhances the sensitivity of NSCLC cells to PI3K/mTOR inhibition
Blockage of Stat3 enhances the sensitivity of NSCLC cells to PI3K/mTOR inhibition
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DOI：
10.1016/j.bbrc.2014.01.086
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发表时间：
2014-02-21
影响因子：
3.1
通讯作者：
Lee, Jin Kyung
中科院分区：
文献类型：
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作者：
Jin, Hyeon-Ok;Lee, Yun-Han;Lee, Jin Kyung
肺癌中的 PI3K/Akt/mTOR 轴经常被激活并与肿瘤发生有关。因此，对该途径的特异性靶向是肺癌的一种有吸引力的治疗方法。然而，非小细胞肺癌细胞对 PI3K 和 mTOR 双重抑制剂 BEZ235 具有耐药性。有趣的是，用选择性抑制剂 S3I-201 或 siRNA 阻断 Stat3 可以显着提高 BEZ235 诱导的细胞死亡的敏感性，这一点从 PARP 裂解增加可以看出。此外，抑制 Stat3 会导致 PI3K 抑制剂 LY294002 诱导的细胞死亡增强。用 BEZ235 和 S3I-201 组合处理细胞显着诱导促凋亡转录因子 CHOP 及其靶标 Bim 和 DR4。 CHOP 或 Bim 的敲低抑制了联合治疗刺激的细胞死亡，表明这些 BEZ235/S3I-201 诱导因子参与了明显的细胞死亡。此外，BEZ235/S3I-201组合增强了TRAIL诱导的细胞死亡。我们的结果总体表明，阻断 Stat3 是克服 PI3K/Akt/mTOR 抑制耐药性的有效策略。 (C) 2014 Elsevier Inc. 保留所有权利。
The PI3K/Akt/mTOR axis in lung cancer is frequently activated and implicated in tumorigenesis. Specific targeting of this pathway is therefore an attractive therapeutic approach for lung cancer. However, non-small cell lung cancer cells are resistant to BEZ235, a dual inhibitor of PI3K and mTOR. Interestingly, blockage of Stat3 with a selective inhibitor, S3I-201, or siRNA dramatically sensitized the BEZ235-induced cell death, as evident from increased PARP cleavage. Furthermore, inhibition of Stat3 led to enhancement of cell death induced by LY294002, a PI3K inhibitor. Treatment of cells with a combination of BEZ235 and S3I-201 significantly induced the proapoptotic transcription factor, CHOP, and its targets, Bim and DR4. Knockdown of CHOP or Bim suppressed cell death stimulated by the combination treatment, implicating the involvement of these BEZ235/S3I-201-induced factors in pronounced cell death. Moreover, the BEZ235/S3I-201 combination enhanced TRAIL-induced cell death. Our results collectively suggest that blockage of Stat3 presents an effective strategy to overcome resistance to PI3K/Akt/mTOR inhibition. (C) 2014 Elsevier Inc. All rights reserved.