Inhibition of eukaryotic translation initiation factor 5A (eIF5A) hypusination impairs melanoma growth

Abstract

The eukaryotic translation initiation factor 5A (eIF5A) undergoes a specific post-translational modification called hypusination. This modification is required for the functionality of this protein. The compound N1-guanyl-1,7-diaminoheptane (GC7) is a potent and selective inhibitor of deoxyhypusine synthase, which catalyses the first step of eIF5A hypusination process. In the present study, the effects of GC7 on cell death were investigated using two cell lines: melan-a murine melanocytes and Tm5 murine melanoma. In vitro treatment with GC7 increased by 3-fold the number of cells presenting DNA fragmentation in Tm5 cells. Exposure to GC7 also decreased viability to both cell lines. This study also describes, for the first time, the in vivo antitumour effect of GC7, as indicated by impaired melanoma growth in C57BL/6 mice.

Involvement of eukaryotic translation initiation factor 5A (eIF5A) in skeletal muscle stem cell differentiation

“…The increase of eIF5A gene expression along the satellite cell differentiation and the higher content of the eIF5A protein after the second day of this process, in comparison to non-differentiated satellite cells and gastrocnemius muscle, indicate a putative requirement of this factor during differentiation of these cells. Previous studies have shown that eIF5A is functionally associated to translation (Kang and Hershey, 1994;Hanauske-Abel et al, 1995;Jao and Chen, 2006) and proliferation processes Tabor and Tabor, 1984;Pegg, 1988;Park et al, 1994;Chen et al, 1996;Shi et al, 1996;Jasiulionis et al, 2007). Kang and Hershey (1994) observed that a rapid depletion of eIF5A in yeast impaired cell proliferation with a partial blockage of protein synthesis.…”

“…Anti-eIF5A polyclonal antibody was obtained as previously described (Parreiras-E-Silva et al, 2007). N1-guanyl-1,7-diamine-heptane (GC7) was obtained as previously described (Jasiulionis et al, 2007). Glycine, ethylenediaminetetraacetic (EDTA), acetic acid, trichloroacetic acid (TCA), sodium chloride (NaCl), magnesium chloride (MgCl 2 ), potassium chloride (KCl), sodium pyrophosphate, chloroform, ethanol, methanol and isopropanol were obtained from Labsynth (Diadema, Brazil (Nuvital, Colombo, Brazil) and water was provided ad libitum.…”

“…Evidences have been observed that eIF5A hypusination is involved with cell proliferation. An increase of hypusine content was observed in lymphocytes stimulated by mitogenic agents and the inhibition of DHS by N1-guanil-1,7-diamino-heptano (GC7) impaired proliferation of different mammalian cell lineages (Jakus et al, 1993;Park et al, 1994;Chen et al, 1996;Shi et al, 1996;Jasiulionis et al, 2007). Other studies associated eIF5A with the transport of macromolecules through nuclear pore complex (Cullen, 1992;Ruhl et al, 1993;Bevec et al, 1996;Schatz et al, 1998;Rosorius et al, 1999;Lipowsky et al, 2000;Hofmann et al, 2001) and with decay of transcripts (Zuk and Jacobson, 1998).…”

The spermidine analogue GC7 (N1-guanyl-1,7-diamineoheptane) induces autophagy through a mechanism not involving the hypusination of eIF5A

“…◂ GC7 is usually used to block the first step of hypusination of eIF5A which leads to the accumulation of the native protein (Landau et al 2010). Interestingly, the treatment with GC7 displays an anticancer effect in various tumours such as neuroblastoma, erythroleukaemia and melanoma (Shi et al 1996;Chen et al 1996;Lee et al 2002;Jasiulionis et al 2007). Lee et al (2009) demonstrated that GC7 inhibits growth and differentiation in oral cancer and immortalized keratinocytes by inducing apoptosis through the mitochondrial and the AMPK pathways (Lee et al 2009).…”

Translation Regulation as a Therapeutic Target in Cancer

“…N1-guanyl-1,7-diaminoheptane (GC7) and ciclopirox olamine (CPX) are potent inhibitors of deoxyhypusine synthase, which catalyzes eIF5A hypusination. GC7 and CPX have shown antiproliferative effects in various cell lines (137,138) and antitumor activity in vivo in breast cancer, melanoma, leukemia, and myeloma models (139)(140)(141).…”