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. This preclinical study lends support to the notion that ovarian cancer management would benefit from administration of minocycline.
Highlights
Uncontrolled activation of NF-kB signaling has been implicated in propagation of a large number of malignancies including ovarian cancer [1, 2]
We have established that minocycline treatment of preclinical models of ovarian cancer modulates specific transcriptional and signal transduction cascades that lead to cell-cycle arrest, apoptosis, and downregulation of angiogenesis and metastasis [10,11,12]
To further confirm the inhibitory effect of minocycline on NF-kB transcriptional activity in vivo, we examined the effect of minocycline on the expression of NF-kB–regulated gene products including Bcl-2 and Bcl-xL, which have been linked to tumor survival; cyclin D1 and c-Myc, which are involved in tumor cell proliferation; and matrix metalloproteinases (MMP)-9 and ICAM-1, which play important roles in metastasis
Summary
Uncontrolled activation of NF-kB signaling has been implicated in propagation of a large number of malignancies including ovarian cancer [1, 2]. There is compelling preclinical evidence that minocycline along with a number of other tetracyclines have potent antitumorigenic and antimetastatic properties in a variety of tumors including leukemia [6], melanoma [7], renal, prostate [8], and breast cancer [9]. Along this line, we have recently reported the preliminary results showing that minocycline inhibits growth of human ovarian cancer xenografts [10, 11] and suppresses ovarian cancer-induced malignant ascites formation [10]. The exact mechanism by which minocycline mediates these www.aacrjournals.org
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