Ramberg Håkon, Eide Turid, Krobert Kurt Allen, Levy Finn Olav, Dizeyi Nishtman, Bjartell Anders S, Abrahamsson Per-Anders, Taskén Kristin Austlid
Faculty Division Aker University Hospital, University of Oslo, Oslo Urological University Clinic, Aker University Hospital, Oslo, Norway.
Prostate. 2008 Jul 1;68(10):1133-42. doi: 10.1002/pros.20778.
Androgen deprivation is the only effective systemic therapy available for patients with prostatic carcinoma, but is associated with a gradual transition to a hormone-refractory prostate cancer (HRCAP) in which ligand-independent activation of the androgen receptor has been implicated. The beta(2)-adrenergic receptor (beta(2)-AR) is a well-known activator of the androgen receptor.
Prostatic cell lines were analyzed using cDNA micro-array, real time RT-PCR, radioligand binding assay, cAMP measurements, transfection and thymidine incorporation assay. Clinical specimens were studied by immunohistochemistry and Affymetrix microarrays.
Here, we show that beta(2)-AR was transiently down-regulated both at mRNA- and protein levels when hormone-sensitive prostate cancer cells, LNCaP, were cultured in steroid stripped medium (charcoal-stripped fetal calf serum) or when the cells were treated with the anti-androgen, bicalutamide (Casodex). The number of beta-adrenergic receptors was modestly up-regulated in androgen independent cell lines (LNCaP-C4, LNCaP-C4-2 and DU145) compared to LNCaP. Triiodothyronine (T3) increased the level of beta(2)-AR and the effect of T3 was inhibited by bicalutamide. Immunohistochemical staining of human prostate specimens showed high expression of beta(2)-AR in glandular, epithelial cells and increased expression in malignant cells compared to benign hyperplasia and normal tissue. Interestingly, beta(2)-AR mRNA was strongly down-regulated by androgen ablation therapy of prostate cancer patients.
The level of beta(2)-AR was increased by T3 in prostatic adenocarcinoma cells and reduced in prostate cancer patients who had received androgen ablation therapy for 3 months.
雄激素剥夺是前列腺癌患者唯一可用的有效全身治疗方法，但会逐渐转变为激素难治性前列腺癌（HRCAP），其中雄激素受体的非配体依赖性激活被认为与此有关。β₂-肾上腺素能受体（β₂-AR）是雄激素受体的知名激活剂。
使用cDNA微阵列、实时逆转录聚合酶链反应、放射性配体结合测定、环磷酸腺苷测量、转染和胸腺嘧啶核苷掺入测定对前列腺细胞系进行分析。通过免疫组织化学和Affymetrix微阵列研究临床标本。
在此，我们表明，当激素敏感的前列腺癌细胞LNCaP在类固醇去除培养基（活性炭去除胎牛血清）中培养时，或当细胞用抗雄激素比卡鲁胺（康士得）处理时，β₂-AR在mRNA和蛋白质水平均短暂下调。与LNCaP相比，雄激素非依赖性细胞系（LNCaP-C4、LNCaP-C4-2和DU145）中β-肾上腺素能受体的数量适度上调。三碘甲状腺原氨酸（T3）增加了β₂-AR的水平，且T3的作用被比卡鲁胺抑制。人前列腺标本的免疫组织化学染色显示，与良性增生和正常组织相比，β₂-AR在腺上皮细胞中高表达，在恶性细胞中表达增加。有趣的是，前列腺癌患者的雄激素消融治疗可使β₂-AR mRNA强烈下调。
T3可增加前列腺腺癌细胞中β₂-AR的水平，而接受雄激素消融治疗3个月的前列腺癌患者中该水平降低。
