Kokontis John M, Hsu Stephen, Chuu Chih-pin, Dang Mai, Fukuchi Junichi, Hiipakka Richard A, Liao Shutsung
Ben May Institute for Cancer Research and the Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, Illinois 60637, USA.
Prostate. 2005 Dec 1;65(4):287-98. doi: 10.1002/pros.20285.
Various studies have implicated the androgen receptor (AR) in the progression of androgen-dependent human prostate cancer cells to androgen-independent and androgen-insensitive phenotypes, but the exact role of AR in progression is unclear.
To mimic the clinical situation and test the role of AR in progression, we cultured androgen-dependent LNCaP 104-S prostate tumor cells in the presence of the antiandrogen Casodex (bicalutamide) to derive resistant (CDXR) clones. In a second step, we cultured CDXR cells in the presence of the androgen R1881, which generated androgen- and Casodex-insensitive (IS) cells. These cells were then characterized with regard to AR function and the effect of ectopic AR expression or AR knockdown on androgen sensitivity.
CDXR cells showed increased AR expression and transcriptional activity. CDXR cell proliferation was unaffected by Casodex but was repressed by androgen in vitro and in vivo. IS cells, on the other hand, had greatly reduced AR expression and activity compared to CDXR cells. Knockdown of AR expression in CDXR cells produced cells that were insensitive to androgen. Conversely, re-expression of AR in IS cells regenerated cells that were repressed by androgen. Knockdown of AR expression in 104-S cells produced cells that remained stimulated by androgen, while overexpression of AR in 104-S cells generated an androgen-repressed phenotype but did not confer androgen-independent growth.
Increased AR expression determines whether prostate cancer cells are repressed by androgen, but is not required for androgen independence. These results may have implications for anti-AR therapy for prostate cancer.
多项研究表明雄激素受体（AR）与雄激素依赖性人前列腺癌细胞向雄激素非依赖性和雄激素不敏感表型的进展有关，但AR在进展过程中的确切作用尚不清楚。
为模拟临床情况并测试AR在进展中的作用，我们在抗雄激素药物康士得（比卡鲁胺）存在的情况下培养雄激素依赖性LNCaP 104-S前列腺肿瘤细胞，以获得耐药（CDXR）克隆。第二步，我们在雄激素R1881存在的情况下培养CDXR细胞，从而产生对雄激素和康士得不敏感（IS）的细胞。然后对这些细胞进行AR功能以及异位AR表达或AR敲低对雄激素敏感性的影响方面的特征分析。
CDXR细胞显示出AR表达和转录活性增加。CDXR细胞的增殖不受康士得影响，但在体外和体内均受雄激素抑制。另一方面，与CDXR细胞相比，IS细胞的AR表达和活性大大降低。在CDXR细胞中敲低AR表达产生了对雄激素不敏感的细胞。相反，在IS细胞中重新表达AR使细胞恢复为受雄激素抑制的状态。在104-S细胞中敲低AR表达产生的细胞仍受雄激素刺激，而在104-S细胞中过表达AR产生了雄激素抑制的表型，但未赋予雄激素非依赖性生长能力。
AR表达增加决定了前列腺癌细胞是否受雄激素抑制，但并非雄激素非依赖性生长所必需。这些结果可能对前列腺癌的抗AR治疗具有启示意义。
