Androgen receptor signaling intensity is a key factor in determining the sensitivity of prostate cancer cells to selenium inhibition of growth and cancer-specific biomarkers
Androgen receptor signaling intensity is a key factor in determining the sensitivity of prostate cancer cells to selenium inhibition of growth and cancer-specific biomarkers
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DOI：
10.1158/1535-7163.mct-05-0124
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发表时间：
2005-07-01
影响因子：
5.7
通讯作者：
Ip, C
中科院分区：
文献类型：
--
作者：
Dong, Y;Zhang, HT;Ip, C
我们先前的报道表明，甲基硒酸(MSA)显著降低LNCaP细胞雄激素受体和前列腺特异性抗原(PSA)的表达。本研究扩展了上述观察结果，揭示了这一现象的普遍性，以及MISA对前列腺癌细胞生长和癌症特异性生物标记物的抑制作用是通过雄激素受体下调来实现的。首先，MSA降低了五种人前列腺癌细胞系(LNCaP、LAPC-4、CWR22Rv1、LNCaPC81和LNCaP-LN3)中雄激素受体和PSA的表达，而与它们的雄激素受体基因(野生型与突变型)或对雄激素刺激生长的敏感性无关。其次，通过ARE-荧光素酶报告基因分析，我们发现MSA抑制雄激素受体反式激活主要是通过降低雄激素受体蛋白水平来实现的。第三，MSA对5个与前列腺癌发生有关的雄激素受体调节基因(PSA、KLK2、ABCC4、DHCR24和GUCY1A3)的抑制作用因雄激素受体的过度表达而显著减弱。第四，雄激素受体导入LNCaP细胞后，MSA对细胞生长和增殖的抑制作用明显减弱。雄激素受体信号在雄激素依赖型和非雄激素依赖型前列腺癌的发生发展过程中发挥着重要作用。我们的研究发现，MSA通过阻断雄激素受体转录来降低雄激素受体的可用性，这为使用硒控制前列腺癌进展的机制驱动干预策略提供了理由。
Our previous report showed that methylseleninic acid (MSA) significantly decreases the expression of androgen receptor and prostate-specific antigen (PSA) in LNCaP cells. The present study extended the above observations by showing the universality of this phenomenon and that the inhibitory effect of MISA on prostate cancer cell growth and cancer-specific biomarkers is mediated through androgen receptor downregulation. First, MSA decreases the expression of androgen receptor and PSA in five human prostate cancer cell lines (LNCaP, LAPC-4, CWR22Rv1, LNCaPC81, and LNCaP-LN3), irrespective of their androgen receptor genotype (wild type versus mutant) or sensitivity to androgen-stimulated growth. Second, by using the ARE-luciferase reporter gene assay, we found that MSA suppression of androgen receptor transactivation is accounted for primarily by the reduction of androgen receptor protein level. Third, MSA inhibition of five androgen receptor-regulated genes implicated in prostate carcinogenesis (PSA, KLK2, ABCC4, DHCR24, and GUCY1A3) is significantly attenuated by androgen receptor overexpression. Fourth, transfection of androgen receptor in LNCaP cells weakened noticeably the inhibitory effect of MSA on cell growth and proliferation. Androgen receptor signaling has been documented extensively to play an important role in the development of both androgen-dependent and -independent prostate cancer. Our finding that MSA reduces androgen receptor availability by blocking androgen receptor transcription provides justification for a mechanism-driven intervention strategy in using selenium to control prostate cancer progression.