Degradation of HER2/neu by apigenin induces apoptosis through cytochrome c release and caspase-3 activation in HER2/neu-overexpressing breast cancer cells.
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.
Way
Tzong-Der
TD
Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, No. 1, Section 1, Jen-ai Road, Taipei 10018, Taiwan.
Kao
Ming-Ching
MC
Lin
Jen-Kun
JK
D047310:Apigenin / Q000494:pharmacology*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000032:analysis / Q000378:metabolism; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000032:analysis / Q000378:metabolism; D056743:Cyclin D3; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000032:analysis / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism*; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011506:Proteins / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000032:analysis / Q000378:metabolism
D047310:Apigenin; D051017:Apoptosis Regulatory Proteins; D053148:Caspase 3; D020169:Caspases; D018797:Cell Cycle Proteins; D019938:Cyclin D1; D056743:Cyclin D3; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins; D045304:Cytochromes c; D005419:Flavonoids; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011506:Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D025521:Tumor Suppressor Proteins; C534696:CCND3 protein, human; C109664:caspase-activated DNase inhibitor; C505407:CASP3 protein, human