Curcumin inhibition of integrin (α₆β₄)- dependent breast cancer cell motility and invasion

Curcumin, a polyphenol natural product isolated from the rhizome of the plant Curcuma longa, has emerged as a promising anticancer therapeutic agent. However, the mechanism by which curcumin inhibits cancer cell functions such as cell growth, survival, and cell motility is largely unknown. We explored whether curcumin affects the function of integrin α6β4, a laminin adhesion receptor with an established role in invasion and migration of cancer cells. Here we show that curcumin significantly reduced α6β4-dependent breast cancer cell motility and invasion in a concentration-dependent manner without affecting apoptosis in MDA-MB-435/β4 (β4-integrin transfectants) and MDA-MB-231 breast cancer cell lines. Further, curcumin selectively reduced the basal phosphorylation of β4 integrin (Y1494), which has been reported to be essential in mediating α6β4-dependent phosphatidylinositol 3-kinase activation and cell motility. Consistent with this finding, curcumin also blocked α6β4-dependent Akt activation and expression of the cell motility-promoting factor ENPP2 in MDA-MB-435/β4 cell line. A multimodality approach using curcumin in combination with other pharmacologic inhibitors of α6β4 signaling pathways showed an additive effect to blockbreast cancer cell motility and invasion. Taken together, these findings show that curcumin inhibits breast cancer cell motility and invasion by directly inhibiting the function of α6β4 integrin, and suggest that curcumin can serve as an effective therapeutic agent in tumors that overexpress α6β4.