Eukaryotic translation initiation factor 5A (eIF-5A) is the only cell
protein that contains the unusual
basic amino acid hypusine [N epsilon-(4-amino-2-hydroxybutyl)
lysine].
Hypusine is formed by the transfer of the butylamine portion from
spermidine to the epsilon-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 anti-
cancer activity of the anti-tumour agents
interferon-alpha (IFN alpha) and
cytosine arabinoside (
ara-C). We have found that IFN alpha 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 IFN alpha 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 IFN alpha on the cytotoxicity of the recombinant toxin
TP40 which inhibits
elongation factor 2, another step of
protein synthesis, through
EGF-R binding and internalisation; IFN alpha 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.