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Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
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Farnesoid X receptor, through the binding with steroidogenic factor 1-responsive element, inhibits aromatase

Stefania Catalano1, Rocco Malivindi, Cinzia Giordano

  • 1Department of Pharmaco-Biology, University of Calabria, 87030 Arcavacata di Rende (CS), Italy

The Journal of Biological Chemistry
|December 23, 2009
PubMed

Insights

Farnesoid X receptor (FXR) activation inhibits aromatase in rat Leydig tumor cells. This FXR-mediated effect, independent of SHP, reduces estrogen production and cell growth, identifying FXR activators as potential therapeutic agents.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Oncology

Background:

  • Farnesoid X receptor (FXR) regulates bile acid homeostasis and is found in non-enterohepatic tissues like the testis.
  • FXR has been identified as a negative modulator of aromatase in human breast cancer cells.
  • Aromatase is crucial for estrogen synthesis, and its dysregulation is implicated in various cancers.

Purpose of the Study:

  • To investigate the role of FXR in regulating aromatase expression and activity in Leydig cells.
  • To determine the mechanism by which FXR modulates aromatase in Leydig tumor cells.
  • To explore the potential anti-proliferative effects of FXR activation in Leydig tumor cells.

Main Methods:

  • Detection of FXR expression in rat Leydig normal and tumor cell lines and testicular tissue.
  • Activation of FXR using chenodeoxycholic acid (CDCA) or GW4064 in R2C Leydig tumor cells.
  • Analysis of aromatase mRNA, protein levels, and enzymatic activity.
  • Reporter gene assays, mutagenesis, electrophoretic mobility shift assays (EMSA), and chromatin immunoprecipitation (ChIP) to elucidate the mechanism of FXR action.
  • Assessment of cell proliferation and estrogen-dependent growth.

Main Results:

  • FXR activation by CDCA or GW4064 down-regulates aromatase expression (mRNA, protein, activity) in rat Leydig tumor cells via a SHP-independent pathway.
  • CDCA reduces basal aromatase promoter activity.
  • FXR competes with steroidogenic factor 1 for binding to the aromatase promoter, inhibiting its activity.
  • FXR activation exhibits anti-proliferative effects on Leydig tumor cells, partly by inhibiting estrogen-dependent growth.

Conclusions:

  • FXR activators are identified as negative modulators of the aromatase enzyme in Leydig tumor cell lines.
  • FXR plays a significant role in regulating estrogen synthesis in testicular Leydig cells.
  • FXR activation may represent a novel therapeutic strategy for estrogen-dependent testicular tumors.

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