Caffeic acid phenethyl ester induces apoptosis by inhibition of NFkappaB and activation of Fas in human breast cancer MCF-7 cells

Masahiko Watabe, Keiichi Hishikawa, Atsushi Takayanagi, Nobuyoshi Shimizu, Toshio Nakaki
Journal of Biological Chemistry 2004 February 13, 279 (7): 6017-26
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.

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