Figure 7

A schematic representation of osteopontin/αvβ3 signaling in the regulation of prostate cancer cell migration. PC3 cells bind osteopontin through integrin αvβ3 in an RGD-dependent manner. Integrin αvβ3 increases Rho GTPase activity through down stream signaling pathway that involves RANKL [62] or tyrosine phosphorylation of several signaling molecules such as Src, PYK2, FAK, and p130^Cas associated with integrin [10,64]. Rho activation increases CD44 surface expression [10,32] that resulted in the activation of MMP-9. The interaction of CD44 with MMP-9 on the cell surface may have a role in the degradation of ECM to facilitate cell migration. Bisphosphonates (BPs) inhibit CD44 surface interaction with MMP-9 either partially or completely. The signaling pathway and the target molecules that exhibit the inhibitory effects of BP treatment are indicated by dotted arrows and 'X'. A decrease (indicated by inverted red arrow) in CD44 surface expression, MMP-9 interaction with CD44 on the cell surface, MMP-9 secretion, and cell migration was observed in cells treated with BP. PC3/OPN cells treated with BPs reproduce the changes observed in PC3/SiRNA and PC3/OPN (RGA) The possible reason for these effects may be due to reduced αvβ3 -signaling in PC3/OPN (RGA) and PC3/SiRNA cells or targeting of αvβ3-signaling pathway by BPs.