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Curcumin Inhibition of Integrin (₆β₄)-Dependent Breast Cancer Cell Motility and Invasion

Authors' Affiliation: Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, Louisiana

Requests for reprints: Jun Chung, Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1501 Kings Highway, P.O. Box 33932, Shreveport, LA 71130. Phone: 318-675-8797; Fax: 318-675-5180; E-mail: jchung{at}lsuhsc.edu.

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 ₆β₄, a laminin adhesion receptor with an established role in invasion and migration of cancer cells. Here we show that curcumin significantly reduced ₆β₄-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 ₆β₄-dependent phosphatidylinositol 3-kinase activation and cell motility. Consistent with this finding, curcumin also blocked ₆β₄-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 ₆β₄ signaling pathways showed an additive effect to block breast 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 ₆β₄ integrin, and suggest that curcumin can serve as an effective therapeutic agent in tumors that overexpress ₆β₄.

Key Words: ₆β₄ integrin • cell motility • invasion • curcumin • Akt