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Degradation of HER2/ neu by apigenin induces apoptosis through cytochrome c release and caspase‐3 activation in HER2/ neu ‐overexpressing breast cancer cells
Author(s) -
Way Tzong-Der,
Kao Ming-Ching,
Lin Jen-Kun
Publication year - 2005
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2004.11.061
Subject(s) - apigenin , apoptosis , chemistry , protein kinase b , cytochrome c , pi3k/akt/mtor pathway , caspase 3 , cyclin d1 , cancer research , microbiology and biotechnology , biochemistry , biology , programmed cell death , cell cycle , flavonoid , antioxidant
We have shown that exposure of the HER2/ neu ‐overexpressing breast cancer cells to apigenin resulted in induction of apoptosis by depleting HER2/ neu protein and, in turn, suppressing the signaling of the HER2/HER3‐PI3K/Akt pathway. Here, we examined whether inhibition of this pathway played a role in the anti‐tumor effect. The results revealed that treatment with apigenin induced apoptosis through cytochrome c release and caused a rapid induction of caspase‐3 activity and stimulated proteolytic cleavage of DFF‐45. Furthermore, apigenin downregulated cyclin D1, D3 and Cdk4 and increased p27 protein levels. Colony formation in the soft agar assay, a hallmark of the transformation phenotype, was preferentially suppressed in HER2/ neu ‐overexpressing breast cancer cells in the presence of apigenin. In addition, a structure–activity relationship study indicated that (1) the position of B ring; and (2) the existence of the 3′, 4′‐hydroxyl group on the 2‐phenyl group were important for the depletion of HER2/ neu protein by flavonoids. These results provided new insights into the structure–activity relationship of flavonoids.