Induction of endoplasmic reticulum stress-mediated apoptosis and non-canonical autophagy by luteolin in NCI-H460 lung carcinoma cells
Induction of endoplasmic reticulum stress-mediated apoptosis and non-canonical autophagy by luteolin in NCI-H460 lung carcinoma cells
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DOI：
10.1016/j.fct.2013.02.022
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发表时间：
2013-06-01
影响因子：
4.3
通讯作者：
Choi, Yung Hyun
中科院分区：
文献类型：
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作者：
Park, Shin-Hyung;Park, Hyun Soo;Choi, Yung Hyun
在这项研究中，我们研究了木犀草素（类黄酮家族的成员）在 NCI-H460 人肺癌细胞中的抗癌作用。结果表明，木犀草素通过调节外源性途径和内源性途径诱导细胞凋亡，而这些途径被 z-VAD-fmk 抑制，表明木犀草素触发 caspase 依赖性细胞凋亡。此外，我们发现真核起始因子2的α亚基（eIF2α/C/EBP同源蛋白通路，而不是c-Jun N末端激酶通路，在木犀草素诱导细胞凋亡中发挥着关键作用。数据表明木犀草素也诱导自噬；证据是微管相关蛋白光的积累 chain-3 (LC3) II 蛋白，LC3 斑点增加以及自噬通量增强。此外，巴弗洛霉素 A1 抑制自噬可减少细胞凋亡，表明木犀草素诱导的自噬是一种细胞死亡机制。值得注意的是，木犀草素处理后出现的活化的半胱天冬酶会裂解 Beclin-1，并且 即使在用 Beclin-1 siRNA 攻击细胞后，LC3II 仍保持不变，这表明木犀草素诱导不依赖于 Beclin-1 的自噬。总而言之，我们的研究结果表明，木犀草素会触发内质网应激相关的细胞凋亡和非典型自噬，这是 NCI-H460 人肺癌细胞的细胞死亡机制。 (C) 2013 爱思唯尔有限公司保留所有权利。
In this study, we investigated the anti-cancer effects of luteolin, a member of the flavonoid family, in NCI-H460 human lung carcinoma cells. It was shown that luteolin induces apoptotic cell death through modulating both the extrinsic pathway and intrinsic pathways, which are suppressed by z-VAD-fmk, indicating that luteolin triggers caspase-dependant apoptosis. Furthermore, we found that the alpha subunit of the eukaryotic initiation factor 2 (eIF2 alpha/C/EBP homologous protein pathway, but not the c-Jun N-terminal kinase pathway, played a critical role in induction of apoptosis by luteolin. The data indicated that luteolin also induces autophagy; evidence for this is the accumulation of microtubule-associated protein light chain-3 (LC3) II protein, the increase of LC3 puncta as well as an enhanced autophagy flux. In addition, inhibiting autophagy by bafilomycin A1 reduced apoptotic cell death, suggesting that luteolin-induced autophagy functions as a cell death mechanism. Notably, the activated caspases that appeared with luteolin treatment cleaved Beclin-1, and the expression of LC3II remained the same even after cells were challenged with Beclin-1 siRNA, demonstrating that luteolin induces Beclin-1-independent autophagy. Taken together, our findings showed that luteolin triggers both endoplasmic reticulum stress-related apoptosis and non-canonical autophagy, which function as a cell death mechanism in NCI-H460 human lung cancer cells. (C) 2013 Elsevier Ltd. All rights reserved.