Prostate cancer mortality is primarily attributed to metastatic rather than primary, organ-confined disease. Acquiring a motile and invasive phenotype is an important step in development of
tumors and ultimately
metastasis. This step involves remodeling of the extracellular matrix and of cell-matrix interactions, cell movement mediated by the actin cytoskeleton, and activation of
focal adhesion kinase (FAK)/Src signaling. Epidemiologic studies suggest that the metastatic behavior of
prostate cancer may be an ideal target for
chemoprevention. The natural
flavone apigenin is known to have chemopreventive properties against many
cancers, including
prostate cancer. Here, we study the effect of
apigenin on motility, invasion, and its mechanism of action in metastatic prostate
carcinoma cells (PC3-M). We found that
apigenin inhibits PC3-M cell motility in a scratch-
wound assay. Live cell imaging studies show that
apigenin diminishes the speed and affects directionality of cell motion. Alterations in the cytoskeleton are consistent with impaired cell movement in
apigenin-treated cells.
Apigenin treatment leads to formation of "exaggerated filopodia," which show accumulation of focal adhesion
proteins at their
tips. Furthermore,
apigenin-treated cells adhere more strongly to the extracellular matrix. Additionally,
apigenin decreases activation of FAK and Src, and phosphorylation of Src substrates FAK Y576/577 and Y925. Expression of constitutively active Src blunts the effect of
apigenin on cell motility and cytoskeleton remodeling. These results show that
apigenin inhibits motility and invasion of prostate
carcinoma cells, disrupts actin cytoskeleton organization, and inhibits FAK/Src signaling. These studies provide mechanistic insight into developing novel strategies for inhibiting
prostate cancer cell motility and invasiveness.