Brucein D modulates MAPK signaling cascade to exert multi-faceted anti-neoplastic actions against breast cancer cells

Abstract

Breast cancer is a prominent type of malignancy among women with a high rate of mortality. A number of previous studies have demonstrated the anticancer potential of brucein D (BD), a quassinoid extracted from Brucea javanica, against the cancers of the pancreas, bone, and liver. We investigated the impact of BD on apoptotic as well on mitogen-activated protein kinase (MAPK) signaling cascades in breast cancer cells. The effect of BD on p38 MAPK and JNK signaling pathways and its downstream functions was deciphered in both MDA-MB-231 and MCF-7 cell lines. We noted that BD decreased the viability of breast cancer cells without affecting the growth of healthy mammary epithelial cells (MCF-10A). Flow cytometric analysis revealed that BD can increase sub-G1 cells and enhanced annexin-V-PI stained cells. The apoptogenic impact of BD was further substantiated by cleavage of procaspase-3/8 and downregulation of antiapoptotic proteins (Bcl-xL, XIAP, and survivin). Furthermore, BD also downmodulated the migratory ability, and chemokine triggered invasion of breast cancer cells. Interestingly, the pharmacological inhibition of p38 MAPK and JNK kinases abrogated the observed anticancer actions of BD. Overall, the data indicated that BD can induce substantial apoptosis and interfere with cellular invasion by modulating MAPK signaling pathway in breast cancer cells.

Keywords: Apoptosis; Breast cancer; Invasion; JNK; Migration; p38 MAPK.