PMS1077 Sensitizes TNF-α Induced Apoptosis in Human Prostate Cancer Cells by Blocking NF-κB 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-κB) 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-α (TNF-α) induced activation of NF-κB signaling. In this study, we found that PMS1077 inhibited TNF-α induced expression of the NF-κB regulated reporter gene in a dose dependent manner. Western blot assay indicated that PMS1077 suppressed the TNF-α induced inhibitor of κB-α (IκB-α) phosphorylation, IκB-α degradation, and p65 phosphorylation. PMS1077 consistently blocked TNF-α induced p65 nuclear translocation as demonstrated in the immunofluorescence assay used. Docking studies by molecular modeling predicted that PMS1077 might interact directly with the IκB kinase-β (IKK-β) subunit. These results suggested that PMS1077 might suppress the activation of NF-κB by targeting IKK-β involved in the NF-κB signaling pathway. Finally, we showed that PMS1077 sensitized cells to TNF-α induced apoptosis by suppressing the expression of NF-κB regulated anti-apoptotic genes. Our results reveal a novel function of PMS1077 on the NF-κB signaling pathway and imply that PMS1077 can be considered as an anti-tumor lead compound.

p-21 activated kinase 4 promotes proliferation and survival of pancreatic cancer cells through AKT- and ERK-dependent activation of NF-κB pathway

“…Our additional data using constitutive active mutant of IKK, an upstream negative regulator of IκB-α provided evidence to support an important role of NF-κB in PAK4-induced growth of PC cells through regulation of proliferation- and survival-associated genes. These findings corroborate other findings where NF-κB has been shown to regulate cell-cycle and apoptosis in other cancer types [34, 39]. …”

IKK inhibitor suppresses epithelial-mesenchymal transition and induces cell death in prostate cancer

“…The kinase subunits of IKK complex have previously been shown to be involved either directly or indirectly in the regulation of cellular proliferation (22). Hence, both IKKα and IKKβ are considered to be therapeutic targets for development of anticancer agents (23,24). However, the precise mechanisms how it is achieved in prostate cancer are only partly understood.…”

Targeted nonviral gene therapy in prostate cancer

“…In addition, studies have discussed the impact of inhibiting NFκB to improve the sensitivity of prostate cancer cells toward TNFα apoptosis by using PMS1077 and apigenin. 68,69 Using a nonviral delivery system, we demonstrated that intravenous administration of Tf-bearing DAB dendriplex encoding TNFα resulted in tumor eradication of 60% of PC3 and 50% of DU145 tumors. 34 This tumor-targeted TNFα gene therapy was more efficacious than TRAIL and IL12, leading to tumor regression and even some tumor disappearance.…”