A role of aryl hydrocarbon receptor in the antiandrogenic effects of polycyclic aromatic hydrocarbons in LNCaP human prostate carcinoma cells.
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 5alpha-dihydrotestosterone (DHT). Chr, BkF and BaP exhibited an antiandrogenic effect, but Ant and Pyr did not. alpha-Naphthoflavone (alpha-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.
Kizu
Ryoichi
R
Graduate School of Natural Science and Technology, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934, Japan. kizu@p.kanazawa-u.ac.jp
Okamura
Kazumasa
K
Toriba
Akira
A
Kakishima
Hiroshi
H
Mizokami
Atsushi
A
Burnstein
Kerry L
KL
Hayakawa
Kazuichi
K
D000726:Androgen Antagonists / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D011084:Polycyclic Aromatic Hydrocarbons / Q000494:pharmacology*; D017430:Prostate-Specific Antigen / Q000096:biosynthesis / Q000235:genetics; D011471:Prostatic Neoplasms / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D011944:Receptors, Androgen / Q000187:drug effects / Q000502:physiology; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000378:metabolism*
D000726:Androgen Antagonists; D011084:Polycyclic Aromatic Hydrocarbons; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D011944:Receptors, Androgen; D018336:Receptors, Aryl Hydrocarbon; D018808:Transcription Factor AP-1; D017430:Prostate-Specific Antigen