A ginseng metabolite, compound K, induces autophagy and apoptosis via generation of reactive oxygen species and activation of JNK in human colon cancer cells.
A ginseng metabolite, compound K, induces autophagy and apoptosis via generation of reactive oxygen species and activation of JNK in human colon cancer cells.
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DOI：
10.1038/cddis.2013.273
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发表时间：
2013-08-01
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
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化合物K（20-O-（β-D-吡喃葡萄糖基）-20（S）-原人参二醇）是人参皂苷的活性代谢物，并在各种类型的癌细胞中诱导凋亡。本研究调查了自噬在化合物K诱导的人HCT-116结肠癌细胞的细胞死亡中的作用。化合物K激活自噬途径，其特征在于囊泡的积累、阳性吖啶橙染色细胞的增加、LC 3-II的积累和自噬通量的升高。而3-甲基腺嘌呤和巴弗洛霉素A1阻断化合物K诱导的自噬显著增加细胞活力。此外，化合物K增强了自噬相关蛋白Atg 5、Atg 6和Atg 7的时间依赖性表达。然而，Atg5、Atg6和Atg7的敲低显著抑制了化合物K对LC 3-II积累和细胞活力的不利影响。化合物K引起的自噬也与细胞内活性氧（ROS）的产生有关;这两个过程都可以通过用抗氧化剂N-乙酰半胱氨酸预处理细胞来减轻。此外，化合物K激活c-Jun NH2-末端激酶（JNK）信号通路，而通过其特异性抑制剂SP600125或通过针对JNK的小干扰RNA下调JNK减弱了响应于化合物K的自噬介导的细胞死亡。化合物K还引起细胞凋亡，如通过增加的凋亡小体和亚G1亚二倍体细胞的数量、增强的半胱天冬酶-3和半胱天冬酶-9的活化以及调节Bcl-2和Bcl-2相关的X蛋白表达所证明的。值得注意的是，化合物K刺激的自噬以及细胞凋亡是通过破坏Atg6和Bcl-2之间的相互作用来诱导的。总之，这些结果表明化合物K诱导的自噬和凋亡是通过人结肠癌细胞中ROS产生和JNK活化介导的。
Compound K (20-O-(β-D-glucopyranosyl)-20(S)-protopanaxadiol) is an active metabolite of ginsenosides and induces apoptosis in various types of cancer cells. This study investigated the role of autophagy in compound K-induced cell death of human HCT-116 colon cancer cells. Compound K activated an autophagy pathway characterized by the accumulation of vesicles, the increased positive acridine orange-stained cells, the accumulation of LC3-II, and the elevation of autophagic flux. Whereas blockade of compound K-induced autophagy by 3-methyladenein and bafilomycin A1 significantly increased cell viability. In addition, compound K augmented the time-dependent expression of the autophagy-related proteins Atg5, Atg6, and Atg7. However, knockdown of Atg5, Atg6, and Atg7 markedly inhibited the detrimental impact of compound K on LC3-II accumulation and cell vitality. Compound K-provoked autophagy was also linked to the generation of intracellular reactive oxygen species (ROS); both of these processes were mitigated by the pre-treatment of cells with the antioxidant N-acetylcysteine. Moreover, compound K activated the c-Jun NH2-terminal kinase (JNK) signaling pathway, whereas downregulation of JNK by its specific inhibitor SP600125 or by small interfering RNA against JNK attenuated autophagy-mediated cell death in response to compound K. Compound K also provoked apoptosis, as evidenced by an increased number of apoptotic bodies and sub-G1 hypodiploid cells, enhanced activation of caspase-3 and caspase-9, and modulation of Bcl-2 and Bcl-2-associated X protein expression. Notably, compound K-stimulated autophagy as well as apoptosis was induced by disrupting the interaction between Atg6 and Bcl-2. Taken together, these results indicate that the induction of autophagy and apoptosis by compound K is mediated through ROS generation and JNK activation in human colon cancer cells.
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