ON-III inhibits erbB-2 tyrosine kinase receptor signal pathway and triggers apoptosis through induction of Bim in breast cancer cells

ErbB-2 gene encodes tyrosine kinase receptor p185neu. Overexpression of erbB-2 plays a key role in tumorigenesis or progression such as breast cancer and ovarian cancer. Our previous study showed that ON-III (2’,4’-dihydroxy-6’-methoxy-3’,5’- dimethylchalcone) extracted from Traditional Chinese Medicine Cleistocaly xoperculatus dry flower could inhibit KDR tyrosine kinase phosphorylation and tumor growth in vivo. In this study, we reported that ON-III repressed tyrosine phosphorylation of  erbB-2 without reduced erbB-2 receptor expression in MDA-MB- 453 cells. Activation of mitogen-activated protein kinase (MAPK) and AKT, downstream molecules of erbB-2-mediated signal transduction pathway, was inhibited following exposure to ON-III. ON-III induced apoptosis in breast cancer cells as determined by caspase-3 and PARP cleavage. Also, ON-III up-regulated the expression of proapoptotic BH3-only Bcl2 family member Bim. Bim siRNA could inhibit ON-III- mediated apoptosis in MDA-MB-453 cells. It concludes that ON-...