Activation of peroxisome proliferator-activated receptor-γ and retinoid X receptor inhibits aromatase transcription via nuclear factor-κB

Wu Qiang Fan, Toshihiko Yanase, Hidetaka Morinaga, Yi Ming Mu, Masatoshi Nomura, Taijiro Okabe, Kiminobu Goto, Nobuhiro Harada, Hajime Nawata

Research output: Contribution to journalArticlepeer-review

82 Citations (Scopus)

Abstract

Our previous studies demonstrated that a peroxisome proliferator-activated receptor (PPAR)-γligand, troglitazone (TGZ), and/or a retinoid X receptor (RXR) ligand, LG1G0268 (LG), decreased the aromatase activity in both cultured human ovarian granulosa cells and human granulosa-like tumor KGN cells. In the present study, we further found that a combined treatment of TGZ+LG decreased aromatase promoter II (ArPII) activity in both ovarian KGN cells and fibroblast NIH-3T3 cells in a PPARγ-dependent manner. Furthermore, the inhibition of both aromatase activity and the transcription of ArPII by TGZ+LG was completely eliminated when nuclear factor-κB (NF-κB) signaling was blocked by specific inhibitors, suggesting NF-κB, which is endogenously expressed in both fibroblast and granulosa cells, might be a mediator of this inhibition. Interestingly, activation of NF-κB by either forced expression of the p65 subunit or NF-κB-inducing kinase up-regulated ArPII activity. Positive regulation of aromatase by endogenous NF-κB was also suggested by the fact that NF-κB-specific inhibitors suppress basal activity of the aromatase gene. A concomitant formation of high-order complex between NF-κB p65 and ArPII was also observed by chromatin immunoprecipitation assay. Although activation of PPARγ and RXR affected endogenous expression levels of neither inhibitory κBα nor p65, it impaired the interaction between NF-κB and ArPII and the p65 based transcription as well. Altogether, these results indicate that activation of a nuclear receptor system, constituted by PPARγ and RXR, down-regulates aromatase expression through the suppression of NF-κB-dependent aromatase activation and thus provide a new insight in the mechanism of regulation of the aromatase gene.

Original languageEnglish
Pages (from-to)85-92
Number of pages8
JournalEndocrinology
Volume146
Issue number1
DOIs
Publication statusPublished - Jan 2005

All Science Journal Classification (ASJC) codes

  • Endocrinology

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