Peng Chiung-Huei, Tseng Tsui-Hwa, Huang Chien-Ning, Hsu Shu-Ping, Wang Chau-Jong
Institute of Biochemistry, Chung Shan Medical University, Chien Kuo N. Road, Taichung 402, Taiwan.
Toxicol Appl Pharmacol. 2005 Jan 15;202(2):172-9. doi: 10.1016/j.taap.2004.06.016.
In our previous study, penta-acetyl geniposide ((AC)(5)GP) is suggested to induce tumor cell apoptosis through the specific activation of PKCdelta. However, the downstream signal pathway of PKCdelta has not yet been investigated. It was shown that JNK may play an important role in the regulation of apoptosis and could be a possible downstream signal of PKCdelta isoforms. In the present study, we investigate whether JNK is involved in (AC)(5)GP induced apoptosis. The result reveals that (AC)(5)GP induces JNK activation and c-Jun phosphorylation thus stimulating the expression of Fas-L and Fas. Using SP600125 to block JNK activation shows that (AC)(5)GP-mediated apoptosis and related proteins expression are attenuated. Furthermore, we find that the (AC)(5)GP induces apoptosis through the activation of JNK/Jun/Fas L/Fas/caspase 8/caspase 3, a mitochondria-independent pathway. The JNK pathway is suggested to be the downstream signal of PKCdelta, since rottlerin impedes (AC)(5)GP-induced JNK activation. Therefore, (AC)(5)GP mediates cell death via activation of PKCdelta/JNK/FasL cascade signaling.
在我们之前的研究中，五乙酰京尼平苷（(AC)(5)GP）被认为可通过特异性激活PKCδ诱导肿瘤细胞凋亡。然而，PKCδ的下游信号通路尚未得到研究。研究表明，JNK可能在细胞凋亡调控中发挥重要作用，并且可能是PKCδ亚型的潜在下游信号。在本研究中，我们探究JNK是否参与(AC)(5)GP诱导的细胞凋亡。结果显示，(AC)(5)GP诱导JNK激活和c-Jun磷酸化，从而刺激Fas-L和Fas的表达。使用SP600125阻断JNK激活表明，(AC)(5)GP介导的细胞凋亡及相关蛋白表达减弱。此外，我们发现(AC)(5)GP通过激活JNK/Jun/Fas L/Fas/caspase 8/caspase 3诱导细胞凋亡，这是一条不依赖线粒体的途径。由于rottlerin可抑制(AC)(5)GP诱导的JNK激活，JNK通路被认为是PKCδ的下游信号。因此，(AC)(5)GP通过激活PKCδ/JNK/FasL级联信号介导细胞死亡。
