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

Abstract

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-III inhibits erbB-2

tyrosine kinase phosphorylation, shuts down its downstream pathway and triggered

apoptosis via induction of Bim. These results suggest that ON-III is a potential novel

anti-cancer agent for erbB-2-overexpressing cancer.