Androgens induce a distinct response of epithelial-mesenchymal transition factors in human prostate cancer cells
Androgens induce a distinct response of epithelial-mesenchymal transition factors in human prostate cancer cells
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DOI：
10.1007/s11010-016-2794-y
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发表时间：
2016-10-01
影响因子：
4.3
通讯作者：
Baniahmad, Aria
中科院分区：
文献类型：
--
作者：
Colditz, Juliane;Rupf, Benjamin;Baniahmad, Aria
雄激素受体（AR）的抑制是前列腺癌（PCa）治疗的主要靶点。然而，长期的雄激素剥夺最终导致去势抵抗性PCa（CRPC）转移和生存率低。新的证据表明，上皮间质转化（EMT）可能促进去势抵抗和前列腺癌的转移。人雄激素依赖性去势敏感性前列腺癌（CSPC）细胞系LNCaP和CRPC细胞系C4-2通常用作人PCa的模型系统。然而，AR的作用和AR拮抗剂（抗雄激素）治疗对EMT关键因子（包括PCa细胞中的长链非编码RNA（lncRNA）DRAIC）的RNA表达的影响仍然难以捉摸。尽管正如预期的那样，在两种细胞系中，已建立的AR靶基因PSA和FKBP 5均被雄激素强烈诱导，但通过短期和长期处理，LNCaP中的E-钙粘蛋白和波形蛋白mRNA水平均被雄激素上调，而在C4-2细胞中则未上调。在两种细胞系中，E-钙粘蛋白和波形蛋白的mRNA水平通过抗雄激素治疗保持不变。调节EMT的转录因子包括Slug、Snail和ZEB 1以及lncRNA DRAIC的表达在两种细胞系中均受到雄激素处理的影响。在两种细胞系中，雄激素上调Slug的mRNA水平，而抗雄激素下调Slug的mRNA水平。另一方面，ZEB 1 mRNA水平强烈上调雄激素，但保持不变的抗雄激素。相反，Snail mRNA水平被雄激素处理抑制，类似于DRAIC RNA水平。然而，虽然抗雄激素治疗似乎没有改变蜗牛mRNA水平，抗雄激素治疗诱导DRAIC RNA水平。此外，尽管Zeb 1 mRNA的强烈上调，但没有观察到ZEB 1蛋白的显著增加，表明尽管雄激素上调，但发生EMT控制转录因子的转录后调节。SLUG蛋白在两种细胞系中均被雄激素增强，并被抗雄激素降低。总之，我们的数据表明，配体激活的AR调节几个EMT关键因子的表达，抗雄激素仅在选定的基因上抵消AR活性。
Inhibition of the androgen receptor (AR) is a major target of prostate cancer (PCa) therapy. However, prolonged androgen deprivation results eventually in castration-resistant PCa (CRPC) with metastasis and poor survival. Emerging evidence suggests that epithelial-mesenchymal transition (EMT) may facilitate castration-resistance and cancer metastasis in PCa. The human androgen-dependent, castration-sensitive prostate cancer (CSPC) cell line LNCaP and the CRPC cell line C4-2 are often used as a model system for human PCa. However, the role of the AR and the effect of AR antagonist (antiandrogen) treatment on the RNA expression of key factors of EMT including the long non-coding RNAs (lncRNAs) DRAIC in PCa cells remain elusive. Although as expected the established AR target genes PSA and FKBP5 are strongly induced by androgens in both cell lines, both E-cadherin and vimentin mRNA levels are upregulated by androgens in LNCaP but not in C4-2 cells by short- and long-term treatments. The mRNA levels of E-cadherin and vimentin remain unchanged by antiandrogen treatment in both cell lines. The expression of transcription factors that regulate EMT including Slug, Snail and ZEB1 and the lncRNA DRAIC were affected by androgen treatment in both cell lines. The mRNA level of Slug is upregulated by androgens and interestingly downregulated by antiandrogens in both cell lines. On the other hand, ZEB1 mRNA levels are strongly upregulated by androgens but remain unchanged by antiandrogens. In contrast, Snail mRNA levels are repressed by androgen treatment similar to DRAIC RNA levels. However, while antiandrogen treatment seems not to change Snail mRNA levels, antiandrogen treatments induce DRAIC RNA levels. Moreover, despite the strong upregulation of Zeb1 mRNA, no significant increase of the ZEB1 protein was observed indicating that despite androgen upregulation, posttranscriptional regulation of EMT controlling transcription factors occurs. SLUG protein was enhanced in both cell lines by androgens and reduced by antiandrogens. Taken together, our data suggest that the ligand-activated AR regulates the expression of several EMT key factors and antiandrogens counteract AR activity only on selected genes.