As shown in Figure ID, OPG drastically attenuated TRAIL induced apoptosis in these tumor cells P 0. 001 To be sure the level of endogenous OPG secreted by CaOV3, OVCAR3 and OVC238A did not contribute to inhibit TRAIL induced apoptosis, we measured the ranges of OPG in conditioned medium from these cells. As shown in Figure IE, the amounts of OPG secreted in conditioned medium had been beneath 1 ng ml whereas the concentration of OPG essential to supply TRAIL safety is 10 ng ml in ovarian cancer cells All with each other, these information recommend that OPG might attenuate TRAIL induced apoptosis inde pendently from its decoy receptor action on TRAIL.
OPG attenuates TRAIL induced apoptosis by an integrin dependent pathway OPG induced endothelial cell proliferation and migration was shown to be mediated by the two av 33 and av 35 integrin suggesting that OPG could activate cell signaling Interestingly, we previously showed that signaling by av 35 integrin attenuated TRAIL induced apoptosis in OC cells Due to the fact these information MP-470 clinical trial suggest read the article that integrins may possibly be involved with OPG mediated inhibition of TRAIL induced apoptosis in ovarian cancer cells, we examined the impact av diminished the protective result of OPG on TRAIL induced apoptosis. The maximal reduction of OPG protection having said that was observed when both blocking antibodies were added together The engagement of integrin to its ligand triggers a signaling cascade that results in the activation of FAK, considered one of the earliest even downstream in integrin signaling Consistent with the function of integrin in OPG mediated attenuation of TRAIL induced apoptosis, we observed that FAK was phosphorylated when OVCAR3 and CaOV3 cells had been incubated with OPG while the levels of complete FAK remained fairly stable We also observed a significant and stronger grow in the phosphorylation of FAK in primary OVC238A cells treated with OPG This could be connected on the differential expres sion of integrins in ovarian cancer cell lines pared to key ovarian cancer specimens Nonetheless, these information recommend that the two av.
OPG induces a rapid phosphorylation of Akt that reaches a peak after thirty min and Akt phosphorylation remained steady for up 120 min In concert with these effects, OPG remedy of OVCAR3 and OVC238A tumor cells also induces Akt phosphorylation Not surprisingly, OPG also induced a dose dependent activation of ERK in CaOV3 cells To even further examine the website link in between OPG mediated Akt activation and TRAIL attenuation, we implemented chemical inhibitors to block the activation within the Akt signaling.