Role of SRC-1 in the promotion of prostate cancer cell growth and tumor progression
Role of SRC-1 in the promotion of prostate cancer cell growth and tumor progression
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DOI：
10.1158/0008-5472.can-04-3541
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发表时间：
2005-09-01
期刊：
影响因子：
11.2
通讯作者：
Weigel, NL
中科院分区：
文献类型：
--
作者：
Agoulnik, IU;Vaid, A;Weigel, NL
前列腺癌最初是雄激素依赖性的，有证据表明雄激素受体在雄激素非依赖性前列腺癌中继续发挥作用。雄激素受体活性取决于雄激素水平和与雄激素受体相互作用的辅激活因子水平。我们的目标是评估雄激素受体共激活剂SRC-1在前列腺癌进展中的作用。使用组织阵列测量SRC-1蛋白水平，我们发现SRC-1在临床定位的雄激素依赖性癌症中的表达增加与肿瘤侵袭性增加的临床和病理变量相关。有趣的是，SRC-1在正常前列腺组织中存在可变表达，其与相应癌组织的染色强度相关。为了测试SRC-1的贡献，我们检查了其在雄激素依赖性LNCaP和雄激素非依赖性C4-2前列腺癌细胞系中的作用。使用小干扰RNA减少雄激素受体的表达，我们发现，雄激素受体是所需的细胞生长和基础表达的前列腺特异性抗原的雄激素非依赖性C4-2细胞系。因此，尽管细胞可以在雄激素耗尽的培养基中生长，但它们仍然依赖雄激素受体。SRC-1表达的减少显著降低了LNCaP和C4-2细胞系的生长并改变了雄激素受体靶基因调控，而对雄激素受体阴性PC-3和DU 145前列腺癌细胞系的生长没有影响。虽然雄激素和雄激素受体在前列腺癌的发展中的需求是明确的，但我们的研究表明，通过SRC-I的表达升高，雄激素受体活性增强，前列腺癌男性患者的疾病更具侵袭性。
Prostate cancer is initially androgen dependent and there is evidence that androgen receptor continues to play a role in androgen-independent prostate cancer. Androgen receptor activity depends both on the level of androgens and on the level of coactivators that interact with androgen receptor. Our goal was to evaluate the role of the androgen receptor coactivator SRC-l in prostate cancer progression. Using tissue arrays to measure SRC-I protein levels, we found that increased SRC-1 expression in clinically localized, androgen-dependent cancer is associated with clinical and pathologic variables of increased tumor aggressiveness. Interestingly, there was variable expression of SRC-1 in normal prostate tissue which correlated with the staining intensity of the corresponding cancer tissue. To test the contribution of SRC-1, we examined its role in androgen-dependent LNCaP and androgen-independent C4-2 prostate cancer cell lines. Using small interfering RNA to reduce expression of androgen receptor, we found that androgen receptor was required both for cell growth and for basal expression of prostate-specific antigen in the androgen-independent C4-2 cell line. Thus, although the cells can grow in an androgen-depleted medium, they remained androgen receptor dependent. Reduction of SRC-1 expression significantly reduced growth and altered androgen receptor target gene regulation in both LNCaP and C4-2 cell lines whereas it had no effect on the growth of the androgen receptor-negative PC-3 and DU145 prostate cancer cell lines. Although the requirement for androgens and androgen receptor in the development of prostate cancer is well established, our study implicates enhanced androgen receptor activity through elevated expression of SRC-I in the development of more aggressive disease in men with prostate cancer.