Inhibition of cell growth through inactivation of eukaryotic translation initiation factor 5A (eIF5A) by deoxyspergualin

Abstract

The mechanism of inhibition of cell growth by deoxyspergualin was studied using mouse mammary carcinoma FM3A cells. Results of studies using deoxyspergualin analogues showed that both the guanidinoheptanate amide and glyoxyspermidine moieties of deoxyspergualin were necessary to cause inhibition of cell growth. When deoxyspergualin was added to the medium, there was a strong inhibition of cell growth and formation of active eukaryotic translation initiation factor 5A (eIF5A) at the third day of culture. There was also a marked decrease in cellular putrescine content and a small decrease in spermidine content. Accumulation of decapped mRNA, which is typically associated with eIF5A deficiency in yeast, was also observed. The inhibition of cell growth and the formation of active eIF5A was not reversed by addition of spermidine. The activity of deoxyhypusine synthase, the first enzyme in the formation of active eIF5A, was inhibited by deoxyspergualin in a cell-free system. These results, taken together, indicate that inhibition of active eIF5A formation is strongly involved in the inhibition of cell growth by deoxyspergualin.

Expression Profiling and Cellular Localization of Genes Associated with the Hair Cycle Induced by Wax Depilation

“…Because its expression is elevated in growing cells, it has been implicated in cell proliferation (Gorlach et al, 1994). The gene product of eIF5A has also been implicated in cell viability and cell proliferation (Nishimura et al, 2002;Park et al, 2003). The hair matrix is considered to be occupied by ''transient amplifying'' cells that proliferate constantly during anagen (Paus et al, 1994;Xu et al, 2003).…”

“…Cathepsin E was expressed in the cuticle of the keratogenous zone. Poly-A-binding protein (PABP)/cytoplasmic 1 (Sachs et al, 1986;Afonina et al, 1998;Deo et al, 1999) and eukaryotic translation initiation factor 5 (eIF5A) (Nishimura et al, 2002) were expressed in germinative hair matrix cells. Cytokeratin 12 was detected in the inner root sheath of the hair bulb.…”

Discovery of Novel Allosteric Inhibitors of Deoxyhypusine Synthase

“…In the second reaction, deoxyhypusine hydroxylase (DOHH) converts the deoxyhypusine-containing intermediate to the hypusine-containing mature eIF5A. This hypusination of eIF5A is critical not only for the proliferation of eukaryotic cells but also for the regulation of protein translation of selected mRNA that are associated with the synthesis of oncoproteins and thus enhances the proliferation of tumor cells. , In addition, a recent publication has reported that eIF5A is involved in cellular respiration and macrophage function by regulating mitochondrial proteins, which can be linked to cancer cell metabolism . Therefore, blocking the biological activity of eIF5A by inhibiting the DHPS-mediated hypusine modification of the eIF5A precursor protein may be a useful strategy that can be employed in the treatment of tumorigenic diseases.…”

Polymethyleneamine Alkaloids of Animal Origin: I. Metabolites of Marine and Microbial Organisms

“…Both the guanidinoheptanoylamide and glyoxyspermidine fragments are necessary for the exertion of this effect. The level of inhibition of the cellular growth is similar in five compounds (LXXX) and (LXXXII)-(LXXXV), whereas the analogue without guanidine group (LXXXVI) and the individual compounds ω-guanidinoheptanoylamide (LXXXVII) and N- [4-(3-aminopropylamino)butyl]-2,2-dihydroxyacetamide (LXXXVIII) do not have such properties [58].…”