Division of Oncology, Center for Applied Medical Research, Department of Histology and Pathology, University of Navarra, Pamplona, Spain.
Prostate. 2011 Jun 1;71(8):824-34. doi: 10.1002/pros.21298. Epub 2010 Nov 17.
Oxidative stress plays a role in prostate cancer (PrCa) initiation and development. Selenoprotein-P (SepP; a protein involved in antioxidant defence) mRNA levels are down-regulated in PrCa. The main goal of our study was to assess whether SepP protects prostate cells from reactive oxygen species (ROS) in prostate carcinogenesis.
Modification of SepP levels and ROS conditions in C3(1)/Tag-derived cell lines representing prostate epithelial neoplasia (PIN) lesions (Pr-111, with high SepP expression); and invasive tumors (Pr-14, with very low SepP expression).
Both Pr-111 and Pr-14 cells express ApoER2 (SepP receptor), which suggests that they may uptake SepP. Pr-14 cells had much higher ROS levels than Pr-111 cells and were highly sensitive to H(2)O(2)-mediated cytotoxicity. When SepP mRNA levels were knocked down with siRNAs in Pr-111 cells, a significant increase in ROS and cell growth inhibition upon H(2)O(2) exposure was found. Subsequent administration of purified SepP in the culture medium of these cells was able to rescue the original phenotype. Similarly, administration of SepP to Pr-14 cells was able to reduce ROS concentrations. Administration of flutamide decreased SepP mRNA levels whereas dihydrotestosterone or synthetic androgens induced SepP expression, indicating the importance of androgens for SepP expression. Immunohistochemical analysis using a PrCa tissue microarray further revealed that SepP protein was reduced in 60.8% prostate tumors compared to benign prostates.
Levels of SepP in prostate cells determine basal ROS levels and sensitivity to H(2)O(2)-induced cytotoxicity. Deregulation of SepP during prostate carcinogenesis may increase free radicals, thus promoting tumor development and de-differentiation.
氧化应激在前列腺癌（PrCa）的发生和发展中起作用。硒蛋白-P（SepP；一种参与抗氧化防御的蛋白质）的 mRNA 水平在 PrCa 中下调。我们研究的主要目的是评估 SepP 是否在前列腺癌发生过程中保护前列腺细胞免受活性氧（ROS）的侵害。
在 C3(1)/Tag 衍生的细胞系中修饰 SepP 水平和 ROS 条件，这些细胞系代表前列腺上皮肿瘤（PIN）病变（具有高 SepP 表达的 Pr-111）；和侵袭性肿瘤（Pr-14，SepP 表达极低）。
Pr-111 和 Pr-14 细胞均表达 ApoER2（SepP 受体），这表明它们可能摄取 SepP。Pr-14 细胞的 ROS 水平比 Pr-111 细胞高得多，并且对 H₂O₂介导的细胞毒性非常敏感。当 Pr-111 细胞中的 SepP mRNA 水平用 siRNAs 敲低时，发现暴露于 H₂O₂时 ROS 显著增加和细胞生长抑制。随后在这些细胞的培养基中添加纯化的 SepP 能够挽救原始表型。同样，向 Pr-14 细胞中添加 SepP 能够降低 ROS 浓度。给予氟他胺可降低 SepP mRNA 水平，而二氢睾酮或合成雄激素诱导 SepP 表达，表明雄激素对 SepP 表达的重要性。使用前列腺癌组织微阵列的免疫组织化学分析进一步表明，与良性前列腺相比，SepP 蛋白在 60.8%的前列腺肿瘤中减少。
前列腺细胞中的 SepP 水平决定了基础 ROS 水平和对 H₂O₂诱导的细胞毒性的敏感性。在前列腺癌发生过程中 SepP 的失调可能会增加自由基，从而促进肿瘤的发展和去分化。
