Post-Translational Modifications of Eukaryotic Initiation Factor-5A (eIF-5a) as a New Target for Anti-Cancer Therapy
Eukaryotic translation initiation factor 5A (eIF-5A) is the only cell protein that contains the unusual basic amino acid hypusine [Nε-(4-amino-2-hydroxybutyl)lysine]. Hypusine is formed by the transfer of the butylamine portion from spermidine to the ε-amino group of a specific lysine residue of eIF-5A precursor and the subsequent hydroxylation at carbon 2 of the incoming 4-aminobutyl moiety. Agents that reduce cell hypusine levels inhibit the growth of mammalian cells. These observations suggest that hypusine is crucial for proliferation and transformation of eukaryotic cells. Here we have studied whether the inhibition of hypusine synthesis can potentiate the anticancer activity of the anti-tumour agents interferon-α (IFNα) and cytosine arabinoside (ara-C). We have found that IFNα increased epidermal growth factor receptor (EGF-R) expression, but reduced S phase and proliferative marker expression in human epidermoid KB cells and that this effect was antagonised by epidermal growth factor (EGF). Growth inhibition induced by IFNα was paralleled by decreased hypusine synthesis and, when EGF counteracted anti-proliferative effects, a reconstitution of hypusine levels was recorded. We also studied the effects of IFNα on the cytotoxicity of the recombinant toxin TP40 which inhibits elongation factor 2, another step of protein synthesis, through EGF-R binding and internalisation; IFNα induced an about 27-fold increase of TP40 cytotoxicity in KB cells.
Ara-C, another antineoplastic agent commonly used in haematologic malignancies, induced both apoptosis and iron depletion in human acute myeloid leukaemic cells. The combination of ara-C and of the iron chelator desferioxamine, a strong inhibitor of hypusine synthesis, had a synergistic activity on apoptosis in these cells. The data strongly suggest that the post-translational modifications of eIF-5A could be a suitable target for the potentiation of the activity of anti-cancer agents.
KeywordsEpidermal Growth Factor Receptor High Performance Liquid Chromatography Epidermal Growth Factor Receptor Expression Haem Iron Cytosine Arabinoside
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- 12.Abbruzzese, A., Park, M.H., and Folk, J.E. (1985) Deoxyhypusine hydroxylase: distribution and partial purification from rat testis. Fed. Proc. 44, 1487.Google Scholar
- 19.Lentini, A., Mattioli, R, Nicolini, L., Pietrini, A., Abbruzzese, A., and Beninati, S. (1997) Anti-invasive effects of theophylline on experimental B16–F10 melanoma lung metastasis. Cancer J. 10, 274–278.Google Scholar
- 22.Abbruzzese, A., Hanauske-Abel, H.M., Park, M.H., Henke, S., and Folk, J.E. (1991) The active site of deoxyhypusyl hydroxylase: use of catecholpeptides and their component chelator and peptide moieties as molecular probes. Biochem. Biophys. Acta 1077, 159–166.Google Scholar
- 25.Budillon, A., Tagliaferri, R, Caraglia, M., Torrisi, M.R., Normanno, N., Iacobelli, S., Palmieri, G., Stoppelli, M.P., Frati, L., and Bianco, A.R. (1991) Upregulation of epidermal growth factor receptor induced by alpha-interferon in human epidermoid cancer cells. Cancer Res. 51, 1294–1299.PubMedGoogle Scholar
- 27.Caraglia, M.,Tagliaferri, R, Correale, R, Genua, G., Pinto, A., Del Vecchio, S., Esposito, G., and Bianco, A.R. (1993) Cytosine arabinoside increases the binding of -labelled epidermal growth factor and [125I]-transferrin and enhances the in vitro targeting of human tumor cells with anti-(growth factor receptor) mAb. Cancer Immunol. Immunother. 37, 150–156.PubMedCrossRefGoogle Scholar
- 28.Caraglia, M., Leardi, A., Improta, S., Perin, V., Ricciardi, B., Arra, C., Ferraro, R, Fabbrocini, A., Pinto, A., Bianco, A.R., and Tagliaferri, P. (1997) Transient exposure to cytarabine increases peptide growth factor receptor expression and tumorigenicity of melanoma cells. Anticancer Res. 17, 2369–2376.PubMedGoogle Scholar
- 31.Caraglia, M., Libroia, A.M., Corradino, S., Coppola, V., Guarrasi, R., Barile, C., Genua, G., Bianco, A.R., and Tagliaferri, P. (1994) “a-Interferon induces depletion of intracellular iron content and upregulation of functional transferrin receptors on human epidermoid cancer KB cells. Biochem. Biophy. Res. Commun. 203, 281–288.CrossRefGoogle Scholar
- 35.Russell, D.H. and Dude, B.G. (1978) Polyamines as Biochemical Markers of Normal and Malignant Growth, 1–178, Raven Press, NY.Google Scholar
- 41.Leardi, A., Caraglia, M., Selleri, C., Pepe, S., Pizzi, C., Notaro, R., Fabbrocini, A., Musicô, M., Abbruzzese, A., Bianco, A.R., and Tagliaferri, P. (1998) desferioxamine increases iron depletion and apoptosis induced by ara-c on human myeloid leukemic cells. Br. J. Haematol. 102, 746–752.PubMedCrossRefGoogle Scholar
- 42.Caraglia, M., Passeggio, A., Beninati, S., Leardi, A., Nicolini, L., Improta, S., Pinto, A., Bianco, A.R., Tagliaferri, P., and Abbruzzese, A. (1997) Interferon a2 recombinant and epidermal growth factor modulate proliferation and hypusine synthesis in human epidermoid cancer KB cells. Biochem. J. 324, 737–741.PubMedGoogle Scholar