Culig Z, Klocker H, Bartsch G, Hobisch A
Department of Urology, University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria.
Endocr Relat Cancer. 2002 Sep;9(3):155-70. doi: 10.1677/erc.0.0090155.
The androgen receptor (AR), a transcription factor that mediates the action of androgens in target tissues, is expressed in nearly all prostate cancers. Carcinoma of the prostate is the most frequently diagnosed neoplasm in men in industrialized countries. Palliative treatment for non-organ-confined prostate cancer aims to down-regulate the concentration of circulating androgen or to block the transcription activation function of the AR. AR function during endocrine therapy was studied in tumor cells LNCaP subjected to long-term steroid depletion; newly generated sublines could be stimulated by lower concentrations of androgen than parental cells and showed up-regulation of AR expression and activity as well as resistance to apoptosis. Androgenic hormones regulate the expression of key cell cycle regulators, cyclin-dependent kinase 2 and 4, and that of the cell cycle inhibitor p27. Inhibition of AR expression could be achieved by potential chemopreventive agents flufenamic acid, resveratrol, quercetin, polyunsaturated fatty acids and interleukin-1beta, and by the application of AR antisense oligonucleotides. In the clinical situation, AR gene amplification and point mutations were reported in patients with metastatic disease. These mutations generate receptors which could be activated by other steroid hormones and non-steroidal antiandrogens. In the absence of androgen, the AR could be activated by various growth-promoting (growth factors, epidermal growth factor receptor-related oncogene HER-2/neu) and pleiotropic (protein kinase A activators, interleukin-6) compounds as well as by inducers of differentiation (phenylbutyrate). AR function is modulated by a number of coactivators and corepressors. The three coactivators, TIF-2, SRC-1 and RAC3, are up-regulated in relapsed prostate cancer. New experimental therapies for prostate cancer are aimed to down-regulate AR expression and to overcome difficulties which occur because of the acquisition of agonistic properties of commonly used antiandrogens.
雄激素受体（AR）是一种介导雄激素在靶组织中作用的转录因子，几乎在所有前列腺癌中均有表达。前列腺癌是工业化国家男性中最常被诊断出的肿瘤。非器官局限性前列腺癌的姑息治疗旨在下调循环雄激素的浓度或阻断AR的转录激活功能。在长期类固醇耗竭的肿瘤细胞LNCaP中研究了内分泌治疗期间的AR功能；新产生的亚系比亲代细胞能被更低浓度的雄激素刺激，并表现出AR表达和活性上调以及对凋亡的抗性。雄激素调节关键细胞周期调节因子细胞周期蛋白依赖性激酶2和4以及细胞周期抑制剂p27的表达。氟芬那酸、白藜芦醇、槲皮素、多不饱和脂肪酸和白细胞介素-1β等潜在化学预防剂以及应用AR反义寡核苷酸均可抑制AR表达。在临床情况下，转移性疾病患者中报道了AR基因扩增和点突变。这些突变产生的受体可被其他类固醇激素和非甾体抗雄激素激活。在没有雄激素的情况下，AR可被多种促生长（生长因子、表皮生长因子受体相关癌基因HER-2/neu）和多效性（蛋白激酶A激活剂、白细胞介素-6）化合物以及分化诱导剂（苯丁酸盐）激活。AR功能受到多种共激活因子和共抑制因子的调节。三种共激活因子TIF-2、SRC-1和RAC3在复发性前列腺癌中上调。前列腺癌的新实验疗法旨在下调AR表达并克服因常用抗雄激素获得激动剂特性而出现的困难。
