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-Keto Acid Metabolites of Naturally Occurring Organoselenium Compounds as Inhibitors of Histone Deacetylase in Human Prostate Cancer Cells

Authors' Affiliations: ¹ Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York, ² Linus Pauling Institute, Oregon State University, Corvallis, Oregon, Departments of ³ Biochemistry and Molecular Biology and ⁴ Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania

Requests for reprints: John Thomas Pinto, Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595. Phone: 914-594-3332; Fax: 914-594-4058; E-mail: john_pinto{at}nymc.edu.

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 -keto acid, β-methylselenopyruvate (MSP), and L-amino acid oxidase converts selenomethionine to its corresponding -keto acid, -keto--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, -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.

Key Words: Prostate cancer • Se-methyl-L-selenocysteine • selenomethionine • HDAC inhibition • glutamine transaminase K • L-amino acid oxidase