Caffeic acid phenethyl ester induces apoptosis by inhibition of NFκB and activation of Fas in human breast cancer MCF-7 cells
Caffeic acid phenethyl ester induces apoptosis by inhibition of NFκB and activation of Fas in human breast cancer MCF-7 cells
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DOI：
10.1074/jbc.m306040200
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发表时间：
2004-02-13
影响因子：
4.8
通讯作者：
Nakaki, T
中科院分区：
文献类型：
--
作者：
Watabe, M;Hishikawa, K;Nakaki, T
转录因子NFkappaB在细胞存活中起作用。凋亡，程序性细胞死亡，通过包括死亡受体配体结合在内的多种触发因素，可被NFkappaB激活拮抗，并因其抑制而增强。在本研究中，我们发现咖啡酸苯乙酯（CAPE）可以抑制NFkappaB，通过Fas信号激活诱导人乳腺癌MCF-7细胞凋亡。CAPE通过Fas配体（Fas- l）不依赖的机制激活Fas，诱导p53调节的Bax蛋白，激活caspase。CAPE还激活了MAPK家族蛋白p38和JNK。SB203580是p38 MAPK的特异性抑制剂，部分抑制CAPE诱导的p53激活、Bax表达和凋亡，这与CAPE导致Bax激活的机制一致，该机制已知由p38和p53调节。显性负c-Jun的表达抑制JNK信号，也抑制cape诱导的细胞凋亡，提示MAPKs参与了cape诱导的细胞凋亡。Fas反义寡聚物的表达与Fas义寡聚物相比，显著抑制了cape诱导的JNK和p38的激活和凋亡。为了确定这些现象是否归因于CAPE对NFkappaB的抑制，我们检查了IkappaBalpha的截断形式（IkappaBDeltaN）缺乏NFkappaB激活所必需的磷酸化位点的影响。表达IkappaBDeltaN不仅能抑制NFkappaB活性，还能诱导Fas活化、Bax表达和细胞凋亡。我们的研究结果表明，NFkappaB抑制足以诱导细胞凋亡，Fas激活在NFkappaB抑制诱导的MCF-7细胞凋亡中起作用。
The transcription factor NFkappaB plays a role in cell survival. Apoptosis, programmed cell death, via numerous triggers including death receptor ligand binding is antagonized by NFkappaB activation and potentiated by its inhibition. In the present study, we found that caffeic acid phenethyl ester (CAPE), known to inhibit NFkappaB, induced apoptosis via Fas signal activation in human breast cancer MCF-7 cells. CAPE activated Fas by a Fas ligand (Fas-L)-independent mechanism, induced p53-regulated Bax protein, and activated caspases. CAPE also activated MAPK family proteins p38 and JNK. SB203580, a specific inhibitor of p38 MAPK, partially suppressed CAPE-induced p53 activation, Bax expression, and apoptosis, consistent with a mechanism by which CAPE leads to Bax activation, known to be regulated by p38 and p53. The expression of dominant negative c-Jun, which inhibits the JNK signal, also suppresses CAPE-induced apoptosis, suggesting MAPKs are involved in CAPE-induced apoptosis. The expression of Fas antisense oligomers significantly suppressed the CAPE-induced activations of JNK and p38 and apoptosis as compared with Fas sense oligomers. To ascertain whether these phenomena are attributable to the inhibition of NFkappaB by CAPE, we examined the effect of a truncated form of IkappaBalpha (IkappaBDeltaN) lacking the phosphorylation sites essential for NFkappaB activation. IkappaBDeltaN expression not only inhibited NFkappaB activity but also induced Fas activation, Bax expression, and apoptosis. Our findings demonstrate that NFkappaB inhibition is sufficient to induce apoptosis and that Fas activation plays a role in NFkappaB inhibition-induced apoptosis in MCF-7 cells.