PMS1077 sensitizes TNF-α induced apoptosis in human prostate cancer cells by blocking NF-κB signaling pathway

PLoS One. 2013 Apr 9;8(4):e61132. doi: 10.1371/journal.pone.0061132. Print 2013.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Apoptosis / genetics
  • Carbamates / chemistry
  • Carbamates / pharmacology*
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Enzyme Activation / drug effects
  • Gene Expression
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genes, Reporter
  • Humans
  • I-kappa B Kinase / chemistry
  • I-kappa B Kinase / metabolism
  • Male
  • Molecular Conformation
  • Molecular Docking Simulation
  • NF-kappa B / metabolism*
  • Phosphorylation / drug effects
  • Piperazines / chemistry
  • Piperazines / pharmacology*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • Protein Binding
  • Protein Transport / drug effects
  • Proteolysis
  • Signal Transduction / drug effects*
  • Transcription Factor RelA / metabolism
  • Transcription, Genetic / drug effects
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • 2-N,N-diethylaminocarbonyloxymethyl-1-diphenylmethyl-4-(3,4,5-trimethoxybenzoyl)piperazine
  • Carbamates
  • NF-kappa B
  • Piperazines
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha
  • I-kappa B Kinase

Grants and funding

This work was supported by the Chun Hui Projects (number Z2009-1-62001, http://www.moe.edu.cn) from the China Ministry of Education and in part by the Science and Technology Support Projects of Gansu Province (number 1104FKCA123, http://www.gsstc.gov.cn), China. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.