Proteomic Profiling of Potential Molecular Targets of Methyl-Selenium Compounds in the Transgenic Adenocarcinoma of Mouse Prostate Model
Proteomic Profiling of Potential Molecular Targets of Methyl-Selenium Compounds in the Transgenic Adenocarcinoma of Mouse Prostate Model
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DOI：
10.1158/1940-6207.capr-09-0261
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发表时间：
2010-08-01
影响因子：
3.3
通讯作者：
Lue, Junxuan
中科院分区：
文献类型：
--
作者：
Zhang, Jinhui;Wang, Lei;Lue, Junxuan
由于硒 (Se) 和维生素 E 癌症预防试验 (SELECT) 未能显示硒代蛋氨酸预防前列腺癌的功效，因此迫切需要为未来的试验确定安全有效的硒形式。我们最近通过口服给药在转基因小鼠前列腺腺癌（TRAMP）模型中显示了甲基硒酸（MSeA）和硒-甲基硒代半胱氨酸（MSeC）的显着预防益处。目前的工作应用 iTRAQ 蛋白质组学方法来分析 TRAMP 前列腺的蛋白质变化，并表征 MSeA 和 MSeC 对其的调节，以确定其潜在的分子靶标。将 18 周龄野生型小鼠和 8 至 18 周龄用水（对照）、MSeA 或 MSeC（3 mg Se/kg）处理的 TRAMP 小鼠的背外侧前列腺合并（每组 9-10 只小鼠）并进行蛋白质提取，然后进行蛋白质变性、还原和烷基化。胰蛋白酶消化后，肽用 iTRAQ 试剂标记，混合在一起，并通过二维液相色谱/串联质谱法进行分析。在可信度 >95% 的 342 个蛋白质中，TRAMP 和野生型小鼠中有 75 个蛋白质的表达存在显着差异。 MSeA 主要影响与前列腺功能分化、雄激素受体信号传导、蛋白质（错误）折叠和内质网应激反应相关的蛋白质，而 MSeC 影响参与 II 期解毒或细胞保护以及基质细胞中的蛋白质。尽管 MSeA 和 MSeC 被认为是甲基硒醇的前体，并且对 TRAMP 模型同样有效，但它们不同的受影响蛋白质谱表明它们的分子靶标的生物学差异超过了相似性。癌症预防研究； 3（8）； 994-1006。 (C) 2010 AACR。
Because the Selenium (Se) and Vitamin E Cancer Prevention Trial (SELECT) failed to show the efficacy of selenomethionine for prostate cancer prevention, there is a critical need to identify safe and efficacious Se forms for future trials. We have recently shown significant preventive benefit of methylseleninic acid (MSeA) and Se-methylselenocysteine (MSeC) in the transgenic adenocarcinoma mouse prostate (TRAMP) model by oral administration. The present work applied iTRAQ proteomic approach to profile protein changes of the TRAMP prostate and to characterize their modulation by MSeA and MSeC to identify their potential molecular targets. Dorsolateral prostates from wild-type mice at 18 weeks of age and TRAMP mice treated with water (control), MSeA, or MSeC (3 mg Se/kg) from 8 to 18 weeks of age were pooled (9-10 mice per group) and subjected to protein extraction, followed by protein denaturation, reduction, and alkylation. After tryptic digestion, the peptides were labeled with iTRAQ reagents, mixed together, and analyzed by two-dimensional liquid chromatography/tandem mass spectrometry. Of 342 proteins identified with >95% confidence, the expression of 75 proteins was significantly different between TRAMP and wild-type mice. MSeA mainly affected proteins related to prostate functional differentiation, androgen receptor signaling, protein (mis) folding, and endoplasmic reticulum-stress responses, whereas MSeC affected proteins involved in phase II detoxification or cytoprotection, and in stromal cells. Although MSeA and MSeC are presumed precursors of methylselenol and were equally effective against the TRAMP model, their distinct affected protein profiles suggest biological differences in their molecular targets outweigh similarities. Cancer Prev Res; 3(8); 994-1006. (C) 2010 AACR.