PMS1077 Sensitizes TNF-[alpha] Induced Apoptosis in Human Prostate Cancer Cells by Blocking NF-[kappa]B Signaling Pathway

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-[kappa]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-[alpha] (TNF-[alpha]) induced activation of NF-[kappa]B signaling. In this study, we found that PMS1077 inhibited TNF-[alpha] induced expression of the NF-[kappa]B regulated reporter gene in a dose dependent manner. Western blot assay indicated that PMS1077 suppressed the TNF-[alpha] induced inhibitor of [kappa]B-[alpha] (I[kappa]B-[alpha]) phosphorylation, I[kappa]B-[alpha] degradation, and p65 phosphorylation. PMS1077 consistently blocked TNF-[alpha] 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[kappa]B kinase-[beta] (IKK-[beta]) subunit. These results suggested that PMS1077 might suppress the activation of NF-[kappa]B by targeting IKK-[beta] involved in the NF-[kappa]B signaling pathway. Finally, we showed that PMS1077 sensitized cells to TNF-[alpha] induced apoptosis by suppressing the expression of NF-[kappa]B regulated anti-apoptotic genes. Our results reveal a novel function of PMS1077 on the NF-[kappa]B signaling pathway and imply that PMS1077 can be considered as an anti-tumor lead compound.