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The eukaryotic initiation factor 5A is involved in the regulation of proliferation and apoptosis induced by interferon-alpha and EGF in human cancer cells.

Abstract
Interferon-alpha (IFNalpha) can induce apoptosis, a process regulated by a complex network of cell factors. Among these, eukaryotic initiation factor-5A (eIF-5A) is peculiar because its activity is modulated by the post-translational formation of the amino acid hypusine. Here we report the effects of IFNalpha and epidermal growth factor (EGF) on apoptosis and eIF-5A activity in human epidermoid oropharyngeal KB and lung H1355 cancer cells. We found that 48-h exposure to 1000 and 2000 IU/ml IFNalpha induced about 50% growth inhibition and apoptosis in H1355 and KB cells, respectively, and the addition of EGF completely antagonized this effect. When IFNalpha induced apoptosis, a hyperactivation of MEK-1 and ERK signalling and a decrease of the hypusine-containing form and, thus, of eIF-5A activity were recorded. The latter effect was again antagonized by the addition of EGF to IFNalpha-pretreated cells, probably through the activation of the EGF-->ERK-dependent pathway, since the addition of the specific MEK-1 inhibitor PD098059 abrogated the recovery of intracellular hypusine content induced by EGF in IFNalpha-pretreated cancer cells. Subsequently, we evaluated if the hypusine synthesis inhibitor (and eIF-5A inactivator) N1-guanyl-1,7-diaminoheptane (GC7) synergized with IFNalpha in the induction of cell growth inhibition and apoptosis. The analysis of the isobologram of IFNalpha and GC7 demonstrated a strong synergism between the two drugs in inducing cell growth inhibition. We also found that GC7 and IFNalpha had a synergistic effect on apoptosis. These data suggest that the apoptosis induced by IFNalpha could be regulated by eIF-5A that, therefore, could represent a useful target for the potentiation of IFNalpha antitumor activity.
AuthorsM Caraglia, M Marra, G Giuberti, A M D'Alessandro, A Baldi, P Tassone, S Venuta, P Tagliaferri, A Abbruzzese
JournalJournal of biochemistry (J Biochem) Vol. 133 Issue 6 Pg. 757-65 (Jun 2003) ISSN: 0021-924X [Print] Japan
PMID12869532 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Drug Combinations
  • Interferon-alpha
  • N(1)-guanyl-1,7-diaminoheptane
  • Peptide Initiation Factors
  • RNA-Binding Proteins
  • eukaryotic translation initiation factor 5A
  • hypusine
  • Guanine
  • Epidermal Growth Factor
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • Lysine
Topics
  • Antineoplastic Agents (pharmacology)
  • Apoptosis
  • Cell Division (drug effects)
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Drug Combinations
  • Epidermal Growth Factor (pharmacology)
  • Guanine (analogs & derivatives, pharmacology)
  • Humans
  • Interferon-alpha (pharmacology)
  • KB Cells
  • Lysine (analogs & derivatives, biosynthesis)
  • MAP Kinase Signaling System (drug effects)
  • Mitogen-Activated Protein Kinase 1 (metabolism)
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases (metabolism)
  • Peptide Initiation Factors (antagonists & inhibitors, metabolism)
  • Phosphorylation
  • Protein Processing, Post-Translational
  • RNA-Binding Proteins

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