PMS1077 sensitizes TNF-? induced apoptosis in human prostate cancer cells by blocking NF-?B signaling pathway.

ABSTRACT: Our previous studies have demonstrated that PMS1077, a platelet-activating factor (PAF) antagonist, could induce apoptosis of Raji cells. However, the mechanism of action has not yet been determined. The nuclear transcription factor-kappa B (NF-?B) signaling pathway plays a critical role in tumor cell survival, proliferation, invasion, metastasis, and angiogenesis, so we determined the effects of PMS1077 and its structural analogs on tumor necrosis factor-? (TNF-?) induced activation of NF-?B signaling. In this study, we found that PMS1077 inhibited TNF-? induced expression of the NF-?B regulated reporter gene in a dose dependent manner. Western blot assay indicated that PMS1077 suppressed the TNF-? induced inhibitor of ?B-? (I?B-?) phosphorylation, I?B-? degradation, and p65 phosphorylation. PMS1077 consistently blocked TNF-? induced p65 nuclear translocation as demonstrated in the immunofluorescence assay used. Docking studies by molecular modeling predicted that PMS1077 might interact directly with the I?B kinase-? (IKK-?) subunit. These results suggested that PMS1077 might suppress the activation of NF-?B by targeting IKK-? involved in the NF-?B signaling pathway. Finally, we showed that PMS1077 sensitized cells to TNF-? induced apoptosis by suppressing the expression of NF-?B regulated anti-apoptotic genes. Our results reveal a novel function of PMS1077 on the NF-?B signaling pathway and imply that PMS1077 can be considered as an anti-tumor lead compound.

SUBMITTER: Shi J 

PROVIDER: S-EPMC3621893 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature