Synthesis of the polyamine catabolic enzyme spermidine/spermine-N1-acetyltransferase (SSAT) has been known to increase rapidly in response to increased polyamines and our new data explain the protein translation control mechanism responsible for this response. We showed that an isoform of nucleolin represses translation by binding to a stem-loop at the extreme 5'end of the mRNA ORF and that this isoform is degraded in cells exposed to exogenous polyamines. This provides negative feedback control in that increased polyamines induce polyamine catabolism. The 5'UTR is also plays a role in that upstream ORF's constitutively suppress translation. Since polyamines are essential for cancer cell growth, deliberate induction of SSAT is an ongoing anti-cancer strategy. Therefore our new knowledge of SSAT translation control presents de-repression as an anti-cancer target, especially for prostate cancer since the polyamine pathway is highly active in this organ. We propose testing the hypothesis that a system to detect SSAT translation de-repression will identify bioactive food compounds with anti-proliferative activity. We plan first t validate an assay we developed based on cells that express SSAT as a fusion protein with a reporter protein. After screening a library using this assay, those compounds found to de-repress SSAT will be examined in secondary screen for anti-proliferative activity.
Our aim i s to identify 8-10 novel compounds that de-repress SSAT and inhibit proliferation of a prostate cancer cell line.
Inhibition of polyamine biosynthesis is the typical approach taken in targeting polyamines in anti-proliferative strategies especially for prostate cancer. Spermidine/spermine-N1-acetyltransferase (SSAT) is known to control polyamines and is translationally repressed. Our aim is to use novel detection system to identify 8-10 novel compounds that de-repress SSAT and inhibit proliferation of a prostate cancer cell line.
|Miller, Barbara A; Hoffman, Nicholas E; Merali, Salim et al. (2014) TRPM2 channels protect against cardiac ischemia-reperfusion injury: role of mitochondria. J Biol Chem 289:7615-29|
|Perez-Leal, Oscar; Abou-Gharbia, Magid; Gordon, John et al. (2014) A novel assay platform for the detection of translation modulators of spermidine/spermine acetyltransferase. Curr Pharm Des 20:245-52|
|Liu, Chunli; Perez-Leal, Oscar; Barrero, Carlos et al. (2013) Modulation of polyamine metabolic flux in adipose tissue alters the accumulation of body fat by affecting glucose homeostasis. Amino Acids :|
|Perez-Leal, Oscar; Barrero, Carlos A; Merali, Salim (2013) Translational control of Nrf2 within the open reading frame. Biochem Biophys Res Commun 437:134-9|