title: Osteoprotegerin (OPG) activates integrin, focal adhesion kinase (FAK), and Akt signaling in ovarian cancer cells to attenuate TRAIL-induced apoptosis.
abstract: 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.
authors.forename: Denis
authors.initials: D
authors.lastname: Lane
authors.forename: Isabelle
authors.initials: I
authors.lastname: Matte
authors.forename: Claude
authors.initials: C
authors.lastname: Laplante
authors.forename: Perrine
authors.initials: P
authors.lastname: Garde-Granger
authors.forename: Claudine
authors.initials: C
authors.lastname: Rancourt
authors.affiliation: Département de Microbiologie et Infectiologie, Université de Sherbrooke, 3001, 12ième Avenue Nord, Sherbrooke, Québec J1H 5 N4, Canada. alain.piche@usherbrooke.ca.
authors.forename: Alain
authors.initials: A
authors.lastname: Piché