BACKGROUND: Resistance to apoptosis is a major problem in ovarian cancer (OC) 
and correlates with poor prognosis. Osteoprotegerin (OPG) is a soluble secreted 
factor that acts as a decoy receptor for receptor activator of NF-κB ligand 
(RANKL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). OPG 
has been reported to attenuate TRAIL-induced apoptosis in a variety of cancer 
cells, including OC cells. OPG-mediated protection against TRAIL has been 
attributed to its decoy receptor function. However, OPG activates integrin/focal 
adhesion kinase (FAK) signaling in endothelial cells. In OC cells, activation of 
integrin/FAK signaling inhibits TRAIL-induced apoptosis. Based on these 
observations, we hypothesized that OPG could attenuate TRAIL-induced apoptosis 
in OC cells through integrin/FAK signaling.
METHODS: In vitro experiments including immunoblots, colony formation assays, 
and apoptosis measurements were used to assess the effect of OPG on 
TRAIL-induced apoptosis.
RESULTS: Exogenous OPG protected from TRAIL-induced apoptosis in a TRAIL 
binding-independent manner and OPG protection was αvβ3 and αvβ5 integrin/FAK 
signaling-dependent. Moreover, OPG-mediated activation of integrin/FAK signaling 
resulted in the activation of Akt. Inhibition of both integrin/FAK and Akt 
signaling significantly inhibited OPG-mediated attenuation of TRAIL-induced 
apoptosis. Although OPG also stimulated ERK1/2 phosphorylation, inhibition of 
ERK1/2 signaling did not significantly altered OPG protection.
CONCLUSIONS: Our studies provide evidence, for the first time, that OPG can 
attenuate TRAIL-induced apoptosis in a TRAIL binding-independent manner through 
the activation of integrin/FAK/Akt signaling in OC cells.