title: 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.
authors.affiliation: School of Life Sciences, Lanzhou University, Lanzhou, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Shi
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Nawal
authors.initials: N
authors.lastname: Serradji
authors.forename: Ximing
authors.initials: X
authors.lastname: Xu
authors.forename: Heng
authors.initials: H
authors.lastname: Zhou
authors.forename: Yinxing
authors.initials: Y
authors.lastname: Ma
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Sun
authors.forename: Peng
authors.initials: P
authors.lastname: Jiang
authors.forename: Yuping
authors.initials: Y
authors.lastname: Du
authors.forename: Jinbo
authors.initials: J
authors.lastname: Yang
authors.forename: Changzhi
authors.initials: C
authors.lastname: Dong
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D051550:I-kappa B Kinase / Q000737:chemistry / Q000378:metabolism; D008297:Male; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis; D015398:Signal Transduction / Q000187:drug effects*; D051996:Transcription Factor RelA / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: C549421:2-N,N-diethylaminocarbonyloxymethyl-1-diphenylmethyl-4-(3,4,5-trimethoxybenzoyl)piperazine; D002219:Carbamates; D016328:NF-kappa B; D010879:Piperazines; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D051550:I-kappa B Kinase