Alendronate, a
nitrogen-containing
bisphosphonate, is a potent inhibitor of
bone resorption used for the treatment and prevention of
osteoporosis. Recent findings suggest that
alendronate and other
nitrogen-containing
bisphosphonates inhibit the
mevalonate pathway and thereby inhibit the synthesis of products derived from this metabolite. This, in turn, prevents the prenylation of a number of
small GTPases, which regulate cell growth, motility, and invasion. We studied the effect of
alendronate on in vitro migration of human
ovarian cancer cells.
Lysophosphatidic acid (LPA) induced a dose-dependent increase of migration of
cancer cells by promoting Rho/
Rho-associated kinase signaling. The induction of
cancer cell migration by LPA was inhibited by the addition of
alendronate in a dose-dependent manner. Treatment of
ovarian cancer cells with
alendronate resulted in inactivation of Rho, changes of cell morphology, loss of stress fiber formation, and focal adhesion assembly, and the suppression of phosphorylation of
myosin light chain and
tyrosine phosphorylation of focal adhesion
proteins, which are essential processes for cell migration. The effects of
alendronate on
cancer cells were prevented by the addition of geranylgeranyol, which is the metabolic intermediate of the
mevalonate pathway. These results suggest that
alendronate inhibits Rho activation by preventing geranylgeranylation, which results in inhibition of LPA-induced migration of human
ovarian cancer cells.