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Eukaryotic Translation Initiation Factor 5A (eIF5A)eIF5A is a translation factor that functions as an elongation factor in protein translation as well as a shuttle protein regulating mRNA transport. eIF5A has been implicated in the regulation of cell growth, apoptosis (cell death), and inflammation (Taylor et al, 2007; Jin et al, 2008; Sun et al, 2010) and is the only mammalian protein where the naturally occurring amino acid, hypusine, is known to occur. The eIF5A gene encodes a lysine containing eIF5A protein that regulates apoptosis. The lysine is converted by a post translational modification into hypusine. The resulting structurally similar hypusine eIF5A protein promotes cell growth and survival. The two proteins possess almost opposite properties and appear to function like a switch to promote either cell death or cell survival, which enables them to play a key role in cancer and inflammation. The regulation of the eIF5A is the basis for the design of SNS01-T, our first product candidate. Our preclinical studies have shown that modulation of unmodified eIF5A kills cancer cells through both the intrinsic (mitochondrial) and the extrinsic (cell death receptor) pathways via activation of MAPK/SAPK signaling pathways, up-regulation of p53, and activation of caspases. Our studies indicate that over-expression of unmodified eIF5A is non-toxic to normal cells. eIF5A is the only known protein to be regulated by the post-translational formation of a hypusine residue. Hypusine modification quickly follows synthesis of the eIF5A precursor and, in dividing cells, almost all of the eIF5A is present in the hypusinated form. Both hypusinated eIF5A and deoxyhypusine synthase, the enzyme that mediates eIF5A hypusination, have been identified as markers of neoplastic growth (Chen et al, 2003; Cracchiolo et al, 2004) and metastasis (Ramaswamy et al, 2003). Hypusinated eIF5A is the predominant form of eIF5A in cancer cells, while an accumulation of unhypusinated eIF5A is generally only observed during apoptosis. Recent studies have indicated that, in its unhypusinated form, eIF5A is pro-apoptotic and thus functionally distinct from hypusine-modified eIF5A (Taylor et al, 2007; Jin et al, 2008). The hypusine modification appears to regulate eIF5A activity by controlling its cellular localization (Lee et al, 2009). In healthy cells, eIF5A is rapidly converted to the hypusinated form and is found primarily in the cytoplasm. By contrast, in response to apoptotic signals, unmodified eIF5A accumulates in the nucleus (Taylor et al, 2007; Jin et al, 2003). In vitro cell studies and in vivo xenograft studies have demonstrated that simultaneous small inhibitory RNA (siRNA)-mediated suppression of hypusinated eIF5A expression and over-expression of a non-hypusinable mutant of eIF5A (eIF5AK50R) potently induces apoptosis in multiple cancer cell types, including myeloma, and inhibits myeloma tumor growth in vivo. eIF5AK50R cannot be hypusinated and mimics the pro-apoptotic actions of unmodified native eIF5A (Taylor et al, 2007; Jin et al, 2008; Sun et al, 2010). Burrows FJ, and Thorpe PE (1994). Vascular targeting--a new approach to the therapy of solid tumors. Pharmacol Ther 64 : 155-174. Chen G, Gharib TG, Thomas DG, Huang CC, Misek DE, Kuick RD, Giordano TJ, Iannettoni MD, Orringer MB, Hanash SM, Beer DG (2003). Proteomic analysis of eIF-5A in lungadenocarcinomas. Proteomics 3 : 496-504. Cracchiolo BM, Heller DS, Clement DMJ, Wolff EC, Park MH and Hanauske-Abel HH (2004). Eukaryotic initiation factor 5A-1 (eIF5A-1) as a diagnostic marker for aberrant proliferation in intraepithelial neoplasia of the vulva. Gynecol Oncol : 94, 217-222. Hideshima T, Chauhan D, Richardson P, Mitsiades C, Mitsiades N, Hayashi T, Munshi N, Dang L, Castro A, Palombella V, Adams J, Anderson KC (2002). NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem 277 :16639-47. Jin BF, He K, Wang HX, Wang J, Zhou T, Lan Y, et al. (2003). Proteomic analysis of ubiquitin-proteasome effects: insight into the function of eukaryotic initiation factor 5A. Oncogene 22 : 4819-4830. Jin S, Taylor CA, Liu Z, Sun Z, Ye B, Thompson JE (2008). Suppression of primary and disseminated murine tumor growth with eIF5A1 gene therapy. Gene Ther Mol Biol 12(B):207-218. Lee SB, Park JH, Kaevel J, Sramkova M, Weigert R, Park MH (2009). The effect of hypusine modification on the intracellular localization of eIF5A. Biochem Biophys Res Commun 383 :497 - 502. Ramaswamy S, Ross KN, Lander ES and Golub TR (2003). A molecular signature of metastasis in primary solid tumors. Nat Genet 33 : 49-54. Sun Z, Cheng Z, Taylor CA, McConkey BJ, Thompson JE (2010). Apoptosis induction by eIF5A1 involves activation of the intrinsic mitochondrial pathway. J Cell Physiol 223 : 798-809. Taylor, CA, Sun, Z, Cliche, DO, Ming, H, Eshaque, B, Jin, S, et al. (2007). Eukaryotic translation initiation factor 5A induces apoptosis in colon cancer cells and associates with the nucleus in response to tumour necrosis factor alpha signalling. Exp Cell Res 313 : 437-449. Back to Top |
