Metastasis is the major cause of breast cancer mortality. The strength of cell adhesion to extracellular matrix is critical to cancer cell migration. Integrins, the primary mediators of cell to extra-cellular matrix adhesion, contain distinct divalent cation-binding sites. Binding of manganese and magnesium is vital to integrin-mediated cancer cell adhesion and migration. We hypothesized that zinc, a divalent cation, can modulate breast cancer metastasis through interfering with these divalent cation-dependent integrin-mediated cancer cell adhesion and migration. MDA-MB-231 cells were cultured in a zinc-depleted medium supplemented with 0 (control), 2.5, 5, 10, 25 and 50 μM of zinc to mimic severe zinc-deficiency, moderate zinc-deficiency, adequate zinc and three levels of zinc-supplementation: low-, moderate- and high-levels of zinc-supplementation, respectively. Zinc treatments had no effect on cellular zinc concentration, cell number and cell viability. Zinc at 5-50 μM reduced migration distance of MDA-MB-231 cells on fibronectin by 43-86% and migration rate on fibronectin by 72-90%. Zinc induced a dose-dependent inhibition of cell adhesion to fibronectin (R(2)=-0.98). Zinc at 10-50 μM reduced magnesium-facilitated cell adhesion to fibronectin in a dose-dependent manner (R(2)=-0.90). However, zinc had no effect on manganese-facilitated cell adhesion to fibronectin. Zinc at 5-50 μM caused rounding of the normally elongated, irregular-shaped MDA-MB-231 cells and disappearance of F-actin. Anti-integrin α5- and β1-subunit blocking antibodies inhibited magnesium-facilitated cell adhesion to fibronectin by 95 and 99%, respectively. In summary, zinc inhibited MDA-MB-231 cell migration on fibronectin by interfering with magnesium-dependent integrin-, likely integrin α5/β1-, mediated adhesion.
Lymburner S, McLeod S, Purtzki M, Roskelley C, Xu Z
J. Nutr. Biochem. 2013 Jun;24(6):1034-40