J. Biochem, 2003, Vol. 133, No. 6 757-765
© 2003 Japanese Biochemical Society
CELL |
The Eukaryotic Initiation Factor 5A Is Involved in the Regulation of Proliferation and Apoptosis Induced by Interferon-
and EGF in Human Cancer Cells
1 Department of Biochemistry and Biophysics, II University of Naples, Via Costantinopoli 16, 80132, Naples; and 2 Department of Experimental Medicine, University "Magna Gr
cia" of Catanzaro, Italy
Interferon-
(IFN) 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 IFN 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 1,000 and 2,000 IU/ml IFN induced about 50% growth inhibition and apoptosis in H1355 and KB cells, respectively, and the addition of EGF completely antagonized this effect. When IFN 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 IFN-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 IFN-pretreated cancer cells. Subsequently, we evaluated if the hypusine synthesis inhibitor (and eIF-5A inactivator) N1-guanyl-1,7-diaminoheptane (GC7) synergized with IFN in the induction of cell growth inhibition and apoptosis. The analysis of the isobologram of IFN and GC7 demonstrated a strong synergism between the two drugs in inducing cell growth inhibition. We also found that GC7 and IFN had a synergistic effect on apoptosis. These data suggest that the apoptosis induced by IFN could be regulated by eIF-5A that, therefore, could represent a useful target for the potentiation of IFN antitumor activity.
+ To whom correspondence should be addressed. Department of Biochemistry and Biophysics, Second University of Naples, Via Costantinopoli, 16 80138 Naples, Italy; Tel: +39-081-5665871, Fax: +39-081-5665863, E-mail: Michele.Caraglia{at}unina2.it
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