アンドロゲン依存性癌細胞増殖における細胞周期制御因子の役割

Abstract

1)前立腺癌のアンドロゲン依存性増殖メカニズムにおける細胞周期制御因子の変化を基礎的に検討した.2)アンドロゲン依存性増殖抑制にはp27とサイクリンD1が, またアンドロゲン受容体を介した転写調節にはサイクリンEが関与していることが示唆された

The functional and quantitative alterations in cell cycle regulators after androgen depletion in an androgen-dependent cancer cell and the interaction between androgen receptor and cell cycle regulators were examined in order to clarify the initial response of cancer cells to anti-androgen therapy. Fluorescence activated cell sorter analysis (FACS) of androgen-dependent cancer cell line (SC-3) cells cultured with or without 1 nM dihydrotestosterone (DHT) revealed that suppression of cell growth after androgen withdrawal was due to G1 arrest. The protein level of cyclin D1 decreased without any apparent change in the amounts of Cdk2, Cdk4, cyclin E or cyclin A. Among various Cdk inhibitors (CKIs) examined, p27 was upregulated at both mRNA and protein levels 24 h after androgen depletion. On the other hand, cyclin E has been shown to increase the transactivation activity of the human androgen receptor (AR) in the presence of DHT. These results suggest that cell cycle regulators are critical targets in the initial response of androgen-dependent cancer cells to androgen depletion and play a key role in the transcriptional activity of AR.