The pivotal role of c-Jun NH2-terminal kinase-mediated Beclin 1 expression during anticancer agents-induced autophagy in cancer cells
The pivotal role of c-Jun NH2-terminal kinase-mediated Beclin 1 expression during anticancer agents-induced autophagy in cancer cells
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DOI：
10.1038/onc.2008.441
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发表时间：
2009-02-01
期刊：
影响因子：
8
通讯作者：
Zhu, X-F
中科院分区：
文献类型：
--
作者：
Li, D-D;Wang, L-L;Zhu, X-F
c-Jun nh2末端激酶（JNK）途径是MAP激酶的一个亚组，主要由细胞因子和环境应激激活。自噬是一种蛋白质降解系统，其特征是形成称为自噬体的双膜液泡。自噬相关基因beclin 1在自噬体形成中起关键作用。然而，JNK通路激活、自噬诱导与Beclin 1表达之间的关系尚不明确。本研究以人癌细胞系CNE2和Hep3B为研究对象，探讨jnk介导的Beclin 1表达在神经酰胺诱导的自噬细胞死亡中的作用。神经酰胺处理后的细胞表现出自噬的特征（即酸性囊泡细胞器的形成和LC3-II的生成）。JNK在这两种暴露于神经酰胺的细胞系中被激活，c-Jun的磷酸化也增加。同时，我们发现神经酰胺上调Beclin 1在癌细胞中的表达。Beclin 1表达上调可被SP600125（一种JNK特异性抑制剂）或针对JNK1/2或c-Jun的小干扰RNA （siRNA）阻断。染色质免疫沉淀和荧光素酶报告基因分析显示，c-Jun参与了神经酰胺治疗对beclin 1转录的调节。此外，SP600125抑制JNK活性可以抑制神经酰胺诱导的自噬。此外，通过siRNA敲低Beclin 1也能抑制神经酰胺介导的自噬细胞死亡。jnk介导的Beclin 1表达也在拓扑替康诱导的自噬中被观察到。这些数据表明，JNK通路的激活可以介导Beclin 1的表达，Beclin 1在癌细胞自噬细胞死亡中起关键作用。
The c-Jun NH2-terminal kinase (JNK) pathway represents one subgroup of MAP kinases that are activated primarily by cytokines and exposure to environmental stress. Autophagy is a protein-degradation system characterized by the formation of double-membrane vacuoles termed autophagosomes. Autophagy-related gene beclin 1 plays a key role in autophagosome formation. However, the relationships between activation of JNK pathway, autophagy induction and Beclin 1 expression remain elusive. In this study, we used human cancer cell lines CNE2 and Hep3B to investigate the role of JNK-mediated Beclin 1 expression in ceramide-induced autophagic cell death. Ceramide-treated cells exhibited the characteristics of autophagy (that is, acidic vesicular organelle formation and the LC3-II generation). JNK was activated in these two cell lines exposed to ceramide and the phosphorylation of c-Jun also increased. In the meantime, we found that ceramide upregulated Beclin 1 expression in cancer cells. The upregulation of Beclin 1 expression could be blocked by SP600125 (a specific inhibitor of JNK) or a small interfering RNA (siRNA) directed against JNK1/2 or c-Jun. Chromatin immunoprecipitation and luciferase reporter analysis revealed that c-Jun was involved in the regulation of beclin 1 transcription in response to ceramide treatment. In addition, inhibition of JNK activity by SP600125 could inhibit autophagy induction by ceramide. Furthermore, Beclin 1 knockdown by siRNA also inhibited ceramide-mediated autophagic cell death. JNK-mediated Beclin 1 expression was also observed in topotecan-induced autophagy. These data suggest that activation of JNK pathway can mediate Beclin 1 expression, which plays a key role in autophagic cell death in cancer cells.