title: Minocycline targets the NF-κB Nexus through suppression of TGF-β1-TAK1-IκB signaling in ovarian cancer.
abstract: Substantial evidence supports the critical role of NF-κB in ovarian cancer. Minocycline, a tetracycline, has been shown to exhibit beneficial effects in this malignancy through regulation of a cohort of genes that overlap significantly with the NF-κB transcriptome. Here, it was examined whether or not the molecular mechanism could be attributed to modulation of NF-κB signaling using a combination of in vitro and in vivo models. Minocycline suppressed constitutive NF-κB activation in OVCAR-3 and SKOV-3 ovarian carcinoma cells and was correlated with attenuation of IκBα kinase (IKK) activation, IκBα phosphorylation and degradation, and p65 phosphorylation and nuclear translocation. The inhibition of IKK was found to be associated with suppression of TGF-β-activated-kinase-1 (TAK1) activation and its dissociation from TAK1-binding-protein-1 (TAB1), an indispensable functional mediator between TGF-β and TAK1. Further studies demonstrated that minocycline downregulated TGF-β1 expression. Enforced TGF-β1 expression induced NF-κB activity, and minocycline rescued this effect. Consistent with this finding, TGF-β1 knockdown suppressed NF-κB activation and abrogated the inhibitory effect of minocycline on this transcription factor. These results suggest that the minocycline-induced suppression of NF-κB activity is mediated, in part, through inhibition of TGF-β1. Furthermore, the influence of minocycline on NF-κB pathway activation was examined in female nude mice harboring intraperitoneal OVCAR-3 tumors. Both acute and chronic administration of minocycline led to suppression of p65 phosphorylation and nuclear translocation accompanied by downregulation of NF-κB activity and endogenous protein levels of its target gene products. These data reveal the therapeutic potential of minocycline as an agent targeting the pro-oncogenic TGF-β-NF-κB axis in ovarian cancer.
  
  
  CONCLUSIONS
  This preclinical study lends support to the notion that ovarian cancer management would benefit from administration of minocycline.
authors.affiliation: Professor and Head of Department of Surgery, Level 3 Pitney Building, St. George Hospital, Gray St., Kogarah, Sydney, NSW 2217, Australia. david.morris@unsw.edu.au.
authors.forename: Parvin
authors.initials: P
authors.lastname: Ataie-Kachoie
authors.forename: Samina
authors.initials: S
authors.lastname: Badar
authors.forename: David L
authors.initials: DL
authors.lastname: Morris
authors.forename: Mohammad H
authors.initials: MH
authors.lastname: Pourgholami
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008911:Minocycline / Q000494:pharmacology*; D058990:Molecular Targeted Therapy / Q000379:methods; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D020672:I-kappa B Proteins; D020930:MAP Kinase Kinase Kinases; D008911:Minocycline; D016328:NF-kappa B; D053773:Transforming Growth Factor beta1; D000099151:MAP Kinase Kinase Kinase 7