A role of aryl hydrocarbon receptor in the antiandrogenic effects of polycyclic aromatic hydrocarbons in LNCaP human prostate carcinoma cells
A role of aryl hydrocarbon receptor in the antiandrogenic effects of polycyclic aromatic hydrocarbons in LNCaP human prostate carcinoma cells
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DOI：
10.1007/s00204-003-0454-y
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发表时间：
2003-06-01
影响因子：
6.1
通讯作者：
Hayakawa, K
中科院分区：
文献类型：
--
作者：
Kizu, R;Okamura, K;Hayakawa, K
在LNCaP细胞中研究了芳烃受体（AhR）在多环芳烃（PAHs）抗雄激素作用中的作用。本研究使用的多环芳烃为：蒽（Chr）、苯并[k]荧蒽（BkF）、苯并[a]芘（BaP）、蒽（Ant）和芘（Pyr）。Chr、BkF和BaP在LNCaP细胞中起AhR激动剂的作用，而Ant和Pyr不起作用。通过5 α -二氢睾酮（DHT）对前列腺特异性抗原（PSA） mRNA和蛋白水平的调控来评价多环芳烃的抗雄激素作用。Chr、BkF和BaP具有抗雄激素作用，而Ant和Pyr没有。alpha-Naphthoflavone (alpha-NF)。一种AhR拮抗剂，逆转了Chr， BkF和BaP的抗雄激素作用，表明需要激活AhR。抗雄激素多环芳烃没有显著降低雄激素受体（AR）水平或细胞DHT浓度。凝胶迁移位移实验显示，Chr、BkF和BaP抑制核提取物中AR与含有AR响应元件（ARE）的寡核苷酸探针的结合，而Ant和Pyr没有影响。抗雄激素PAHs升高c-fos和c-jun的mRNA水平。由于活化蛋白-1 （AP-1）是c-jun和c-fos蛋白的异源二聚体，已知可通过与AR的蛋白-蛋白相互作用抑制AR与ARE的结合，本研究的发现提示AP-1可能参与了PAHs作为AhR激动剂的抗雄激素作用。这些结果表明，AhR可以刺激AP-1的表达，从而抑制PSA等靶基因转录调控区AR与ARE的结合。
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.