Minocycline Targets the NF-κB Nexus through Suppression of TGF-β1-TAK1-IκB Signaling in Ovarian Cancer

Substantial evidence supports the critical role of NF-kappa B 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-kappa B transcriptome. Here, it was examined whether or not the molecular mechanism could be attributed to modulation of NF-kappa B signaling using a combination of in vitro and in vivo models. Minocycline suppressed constitutive NF-kappa B activation in OVCAR-3 and SKOV-3 ovarian carcinoma cells and was correlated with attenuation of I kappa B alpha kinase (IKK) activation, I kappa B alpha phosphorylation and degradation, and p65 phosphorylation and nuclear translocation. The inhibition of IKK was found to be associated with suppression of TGF-beta-activated-kinase-1 (TAK1) activation and its dissociation from TAK1-binding-protein-1 (TAB1), an indispensable functional mediator between TGF-beta and TAK1. Further studies demonstrated that minocycline downregulated TGF-beta 1 expression. Enforced TGF-beta 1 expression induced NF-kappa B activity, and minocycline rescued this effect. Consistent with this finding, TGF-beta 1 knockdown suppressed NF-kappa B activation and abrogated the inhibitory effect of minocycline on this transcription factor. These results suggest that the minocycline-induced suppression of NF-kappa B activity is mediated, in part, through inhibition of TGF-beta 1. Furthermore, the influence of minocycline on NF-kappa B 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-kappa B 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-beta-NF-kappa B axis in ovarian cancer. Implications: This preclinical study lends support to the notion that ovarian cancer management would benefit from administration of minocycline.