A role of aryl hydrocarbon receptor in the antiandrogenic effects of polycyclic aromatic hydrocarbons in LNCaP human prostate carcinoma cells

Ryoichi Kizu, Kazumasa Okamura, Akira Toriba, Hiroshi Kakishima, Atsushi Mizokami, Kerry L. Burnstein, Kazuichi Hayakawa

Research output: Contribution to journalArticle

89 Scopus citations

Abstract

The role of aryl hydrocarbon receptor (AhR) on the antiandrogenic effects of polycyclic aromatic hydrocarbons (PAHs) was studied in LNCaP cells. The PAHs used in this study were chrysene (Chr), benzo[k]fluoranthene (BkF), benzo[a]pyrene (BaP), anthracene (Ant) and pyrene (Pyr). Chr, BkF and BaP acted as AhR agonists in LNCaP cells, while Ant and Pyr did not. The antiandrogenic effects of the PAHs were evaluated on the basis of regulation of prostate-specific antigen (PSA) mRNA and protein levels by 5α-dihydrotestosterone (DHT). Chr, BkF and BaP exhibited an antiandrogenic effect, but Ant and Pyr did not. α-Naphthoflavone (α-NF), an AhR antagonist, reversed the antiandrogen action of Chr, BkF and BaP, suggesting a requirement for activated AhR. The antiandrogenic PAHs did not significantly decrease androgen receptor (AR) levels or cellular DHT concentrations. Gel mobility shift assays revealed that Chr, BkF and BaP inhibited the binding of AR in nuclear extracts to oligonucleotide probes containing the AR-responsive element (ARE), whereas Ant and Pyr had no effect. The antiandrogenic PAHs elevated mRNA levels of c-fos and c-jun. Since activator protein-1 (AP-1), a heterodimer of c-jun and c-fos proteins, is known to inhibit binding of AR to ARE by protein-protein interaction with AR, the findings in the present study suggest a possible involvement of AP-1 in the antiandrogenic effects of PAHs acting as AhR agonists. These results suggest that AhR can stimulate AP-1 expression resulting in inhibition of the binding of AR to ARE in the transcription regulatory region of target genes such as PSA.

Original languageEnglish (US)
Pages (from-to)335-343
Number of pages9
JournalArchives of Toxicology
Volume77
Issue number6
DOIs
StatePublished - Jun 1 2003

Keywords

  • Activator protein-1
  • Androgen receptor
  • Antiandrogenic effect
  • Aryl hydrocarbon receptor
  • Polycyclic aromatic hydrocarbon

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

Fingerprint Dive into the research topics of 'A role of aryl hydrocarbon receptor in the antiandrogenic effects of polycyclic aromatic hydrocarbons in LNCaP human prostate carcinoma cells'. Together they form a unique fingerprint.

  • Cite this