Lee Jeong-In, Nian Hui, Cooper Arthur J L, Sinha Raghu, Dai Jenny, Bisson William H, Dashwood Roderick H, Pinto John T
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA.
Cancer Prev Res (Phila). 2009 Jul;2(7):683-93. doi: 10.1158/1940-6207.CAPR-09-0047.
Histone deacetylase (HDAC) inhibitors are gaining interest as cancer therapeutic agents. We tested the hypothesis that natural organoselenium compounds might be metabolized to HDAC inhibitors in human prostate cancer cells. Se-Methyl-L-selenocysteine (MSC) and selenomethionine are amino acid components of selenium-enriched yeast. In a cell-free system, glutamine transaminase K (GTK) and L-amino acid oxidase convert MSC to the corresponding alpha-keto acid, beta-methylselenopyruvate (MSP), and L-amino acid oxidase converts selenomethionine to its corresponding alpha-keto acid, alpha-keto-gamma-methylselenobutyrate (KMSB). Although methionine (sulfur analogue of selenomethionine) is an excellent substrate for GTK, selenomethionine is poorly metabolized. Structurally, MSP and KMSB resemble the known HDAC inhibitor butyrate. We examined androgen-responsive LNCaP cells and androgen-independent LNCaP C4-2, PC-3, and DU145 cells and found that these human prostate cancer cells exhibit endogenous GTK activities. In the corresponding cytosolic extracts, the metabolism of MSC was accompanied by the concomitant formation of MSP. In MSP-treated and KMSB-treated prostate cancer cell lines, acetylated histone 3 levels increased within 5 hours, and returned to essentially baseline levels by 24 hours, suggesting a rapid, transient induction of histone acetylation. In an in vitro HDAC activity assay, the selenoamino acids, MSC and selenomethionine, had no effect at concentrations up to 2.5 mmol/L, whereas MSP and KMSB both inhibited HDAC activity. We conclude that, in addition to targeting redox-sensitive signaling proteins and transcription factors, alpha-keto acid metabolites of MSC and selenomethionine can alter HDAC activity and histone acetylation status. These findings provide a potential new paradigm by which naturally occurring organoselenium might prevent the progression of human prostate cancer.
组蛋白去乙酰化酶（HDAC）抑制剂作为癌症治疗药物正受到越来越多的关注。我们验证了一个假设，即天然有机硒化合物可能在人前列腺癌细胞中代谢为HDAC抑制剂。硒代甲基-L-硒代半胱氨酸（MSC）和硒代蛋氨酸是富硒酵母的氨基酸成分。在无细胞体系中，谷氨酰胺转氨酶K（GTK）和L-氨基酸氧化酶将MSC转化为相应的α-酮酸，即β-甲基硒代丙酮酸（MSP），而L-氨基酸氧化酶将硒代蛋氨酸转化为其相应的α-酮酸，即α-酮基-γ-甲基硒代丁酸（KMSB）。虽然蛋氨酸（硒代蛋氨酸的硫类似物）是GTK的优良底物，但硒代蛋氨酸的代谢较差。从结构上看，MSP和KMSB类似于已知的HDAC抑制剂丁酸。我们检测了雄激素反应性LNCaP细胞以及雄激素非依赖性LNCaP C4-2、PC-3和DU145细胞，发现这些人前列腺癌细胞表现出内源性GTK活性。在相应的胞质提取物中，MSC的代谢伴随着MSP的同时形成。在MSP处理和KMSB处理的前列腺癌细胞系中，乙酰化组蛋白3水平在5小时内升高，并在24小时时基本恢复到基线水平，这表明组蛋白乙酰化有快速、短暂的诱导。在体外HDAC活性测定中，硒代氨基酸MSC和硒代蛋氨酸在浓度高达2.5 mmol/L时没有作用，而MSP和KMSB均抑制HDAC活性。我们得出结论，除了靶向氧化还原敏感的信号蛋白和转录因子外，MSC和硒代蛋氨酸的α-酮酸代谢产物还可以改变HDAC活性和组蛋白乙酰化状态。这些发现提供了一种潜在的新范例，通过它天然存在的有机硒可能预防人类前列腺癌的进展。
