Pravettoni A, Mornati O, Martini P G V, Marino M, Colciago A, Celotti F, Motta M, Negri-Cesi P
Department of Endocrinology, Center for Endocrinological Oncology, University of Milano, via Balzaretti 9, 20133 Milano, Italy.
Mol Cell Endocrinol. 2007 Jan 15;263(1-2):46-54. doi: 10.1016/j.mce.2006.08.008. Epub 2006 Oct 4.
Estrogen receptor beta (ERbeta) plays a protective role against uncontrolled cell proliferation. ERbeta is lost during prostate cancer (CaP) progression suggesting its direct involvement in contrasting tumor proliferation in this disease; however, the molecular mechanism at the basis of this effect has not been clearly defined yet. Possible molecular targets of ERbeta were assessed in DU145 cells, a CaP cell line expressing only ERbeta. Cells treated from 1 to 9 days with different doses of estradiol or diarylpropionitrile (DPN, an ERbeta-selective agonist) show a time-dependent decrease in cell proliferation. The reduced proliferation rate is accompanied by the stimulation of ERbeta expression and the increase of cyclin-dependent kinase inhibitor p21. We demonstrate that the endogenous ERbeta is one of the mediator of the antiproliferative action of estrogens enhancing the synthesis of molecules such as p21 that control cell cycle, an effect amplified by the autoregulation of ERbeta expression. Our observations suggest that CaP, when expressing a functional ERbeta, might be sensitive to the antiproliferative action of estrogens; therefore, ERbeta specific agonists might be valid candidates for new pharmacological approaches to this disease.
雌激素受体β（ERβ）对失控的细胞增殖起保护作用。在前列腺癌（CaP）进展过程中，ERβ会缺失，这表明它直接参与抑制该疾病中的肿瘤增殖；然而，这种作用背后的分子机制尚未明确界定。在仅表达ERβ的CaP细胞系DU145细胞中评估了ERβ可能的分子靶点。用不同剂量的雌二醇或二芳基丙腈（DPN，一种ERβ选择性激动剂）处理细胞1至9天，结果显示细胞增殖呈时间依赖性下降。增殖率降低伴随着ERβ表达的刺激和细胞周期蛋白依赖性激酶抑制剂p21的增加。我们证明内源性ERβ是雌激素抗增殖作用的介质之一，可增强诸如p21等控制细胞周期的分子的合成，ERβ表达的自动调节会放大这种效应。我们的观察结果表明，表达功能性ERβ的CaP可能对雌激素的抗增殖作用敏感；因此，ERβ特异性激动剂可能是针对这种疾病的新药理学方法的有效候选物。
