HORMONAL-REGULATION OF PROSTATE-SPECIFIC ANTIGEN (PSA) GLYCOPROTEIN IN THE HUMAN PROSTATIC ADENOCARCINOMA CELL-LINE, LNCAP
HORMONAL-REGULATION OF PROSTATE-SPECIFIC ANTIGEN (PSA) GLYCOPROTEIN IN THE HUMAN PROSTATIC ADENOCARCINOMA CELL-LINE, LNCAP
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DOI：
10.1002/pros.2990210107
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发表时间：
1992-01-01
期刊：
影响因子：
2.8
通讯作者：
TINDALL, DJ
中科院分区：
文献类型：
--
作者：
MONTGOMERY, BT;YOUNG, CYF;TINDALL, DJ
前列腺特异性抗原（PSA）已成为前列腺癌患者管理的最有用的标志物。这种糖蛋白在体内的调节具有重要的临床意义。间接证据表明PSA糖蛋白可能受雄激素调节，本实验室先前的研究表明PSA mRNA受雄激素上调。目前的工作报告了一个详细的研究PSA糖蛋白表达的影响类固醇激素在人前列腺腺癌细胞系，LNCaP。首先，我们研究了该细胞系中雄激素受体的类固醇结合特异性。与前列腺中的野生型大鼠雄激素受体相比，LNCaP细胞中的受体对许多类固醇或类似物如孕酮（R5020）、抗孕酮（RU 486）、两种抗雄激素（醋酸环哌孕酮和羟氟孕酮）和雄激素代谢物（epitetamine）具有改变的亲和力。然而，其对雄激素（米勃龙、双氢睾酮和睾酮）的亲和力不变。该受体不与合成糖皮质激素（曲安奈德和地塞米松）结合，也不与合成雌激素DES（己烯雌酚）结合。受体的类固醇结合特异性的变化与受体的类固醇结合结构域的单个突变（相对于起始密码子，在核苷酸#876处的A -> G）相关。雄激素受体的类固醇结合特异性的突变和改变也与受测试的不同配体影响的PSA糖蛋白表达相关。我们已经证明PSA糖蛋白被雄激素上调，并且不受表皮生长因子和碱性成纤维细胞生长因子的影响。R5020、雌二醇和表阿霉素均可诱导PSA糖蛋白的表达，但糖皮质激素和DES对PSA的诱导无影响。有趣的是，尽管抗雄激素药物醋酸环哌酮具有诱导PSA的能力，但RU 486和羟基氟替卡松都可以阻断雄激素和孕酮对PSA糖蛋白的诱导。因此，我们得出结论，PSA糖蛋白的表达主要是通过其受体的雄激素的影响，和受体的突变可以影响该细胞基因的表达，雄激素以外的类固醇。
Prostate-specific antigen (PSA) has emerged as the most useful marker for management of patients with prostate cancer. The regulation of this glycoprotein in vivo has important clinical implications. Indirect evidence indicates that the PSA glycoprotein might be regulated by androgens, and previous studies in this laboratory have demonstrated that PSA mRNA is upregulated by androgens. The current work reports a detailed study of PSA glycoprotein expression as influenced by steroid hormones in a human prostatic adenocarcinoma cell line, LNCaP. First, we have examined the steroid binding specificity of the androgen receptor in this cell line. In comparison with wild-type rat androgen receptor in prostate, the receptor in LNCaP cells has altered affinity for a number of steroids or analogs such as progesterone (R5020), antiprogesterone (RU486), two antiandrogens (cyperoterone acetate and hydroxyflutamide), and an androgen metabolite (epitestosterone). However, its affinity for androgens (mibolerone, dihydrotestosterone, and testosterone) is not changed. The receptor does not bind to the synthetic glucocorticoids (triaminolone acetonide and dexamethasone) nor to a synthetic estrogen DES (diethylstilbestrol). The change of the steroid binding specificity of the receptor is correlated with a single mutation (A --> G at nucleotide #876 relative to die initiation codon) of the steroid binding domain of the receptor. The mutation and alteration of steroid-binding specificity of the androgen receptor is also correlated with PSA glycoprotein expression affected by different ligands tested. We have demonstrated that the PSA glycoprotein is upregulated by androgens and is affected by neither epidermal growth factor nor basic fibroblast growth factor. Moreover, PSA glycoprotein could be induced by R5020, estradiol, and epitestosterone; but neither glucocorticoids nor DES had any effect on PSA induction. Interestingly, although the antiandrogen, cyperotone acetate, had the ability to induce PSA, both RU486 and hydroxyflutamide could block androgen and progesterone induction of PSA glycoprotein. Therefore, we conclude that the PSA glycoprotein expression is influenced predominantly by androgens via its receptor, and the mutation of the receptor can affect the expression of this cellular gene by the steroids other than androgens.