Abstract 3778: Protein targets for prostate cancer prevention by α-keto acid metabolites of organoselenium compounds

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Our previous studies show that human glutamine transaminase K (GTK) and L-amino acid oxidase convert Se-methylselenocysteine (MSC) and selenomethionine (SM) to methylselenopyruvate (MSP) and α-keto-γ-methylselenobutyrate (KMSB), respectively. Further more, both of these α-seleno keto acids inhibit histone deacetylase (HDAC) activity in cultured human prostate cancer cells in a dose-dependent manner (Cancer Prev. Res. 2:683, 2009). Since human prostate cancer cells have GTK activity and can metabolize MSC to MSP but not SM to KMSB, we studied whether administration of SM and KMSB to human prostate cancer cells each function as direct-acting metabolites of organoselenium compounds and individually can result in differential regulation of protein targets critical for growth regulation. Using a 4-plex-iTRAQ proteomic approach, we examined the potential effects of either SM or KMSB on several protein targets in LNCaP prostate cancer cells. Analyses revealed significant changes (p<0.05) in at least 68 proteins (1-60 peptide residue coverage) following 5 hr incubation of LNCaP cells with SM (200 μM), KMSB (50 μM) and Trichostatin A (TSA) (20 μM), an inhibitor of class I and II mammalian HDACs. The majority of observed protein changes were cytosolic (49%), nuclear (31%), then plasma membrane (4%) and the remainder was extracellular or unknown. Six proteins that included histone 1c, histone 2a, PARP1, and Epoxide hydrolase 1 microsomal (xenobiotic) were up regulated and two proteins, namely, ribosomal protein SA and hematological and neurological expressed-1 protein were down regulated in both KMSB and TSA-treated cells. A total of six proteins (including annexin VI and splicing factor 3a) were significantly altered by KMSB treatment alone while fifteen proteins (among which HSP90, 14-3-3e, phosphoglycerate kinase 1, and eukaryotic translation initiation factor 4γ) were significantly changed by SM treatment alone. Collectively, our data reveal that several novel protein targets for prostate cancer prevention may be selective for either KMSB or SM alone. Several of these recognized targets will be investigated further to confirm the selectivity of seleno amino acids or seleno keto acids to function as direct-acting metabolites of naturally-occurring organoselenium compounds that can lead to de-repression of silenced tumor suppressor proteins and/or regulation of genes and signal factors. The study was supported by NCI R01CA111842. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3778.