N¹‐guanyl‐1,7,‐diamineoheptane, an inhibitor of deoxyhypusine synthase, suppresses differentiation and induces apoptosis via mitochondrial and AMPK pathways in immortalized and malignant human oral keratinocytes

Abstract

These results demonstrate that GC7 blocks immortalized and malignant keratinocyte cell proliferation and differentiation by inducing apoptosis through the mitochondrial and AMPK pathways. On the basis of these observations, we propose that a strategy combining GC7 and AMPK inhibition could be developed into a novel chemotherapeutic modality in oral cancer.

Drug-Induced Reactivation of Apoptosis Abrogates HIV-1 Infection

“…Specifically, a pharmacologically [22], [23], [41]–[46], [52]–[54] or genetically [47]–[49] induced defect of hypusine-containing eIF5A in culture both activates apoptosis in susceptible cells [22], [41]–[48] and inhibits infection by human [22], [23], [49], [52], [53] or feline [54] immunodeficiency virus. Although CPX and DEF could affect other pathways, as discussed below, our data support the view that DOHH and the posttranslational modification of eIF5A are the relevant targets for both drugs.…”

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

“…The GC7 off-target effect we demonstrated in this study is particularly relevant considering that this drug has been proposed as an important candidate for the therapy of cancer, diabetes and HIV infection. Indeed, eIF5A plays an important role in protein translation since disruption of the hypusination process by GC7 has been shown to inhibit the growth of many cancer cell types as well as endothelial cells (Lee et al 2009(Lee et al , 2010Caraglia et al 2003). For example, in hepatocellular carcinoma, over-expression of eIF5A2 was reported to be associated with tumour features that indicate poor prognosis, such as the presence of tumour metastasis and venous infiltration (Lee et al 2010).…”

“…Spermidine plays a pivotal role in the post-translational modification of the eukaryotic initiation factor 5A (eIF5A) since it is the essential substrate for the protein hypusination (Huang et al 2007). Under physiological conditions eIF5A is constitutively hypusinated, but its activity and subcellular localization can be conditioned by reversible acetylation (Lee et al 2009;Ishfaq et al 2012). PCAF is the major cellular acetyltransferase of eIF5A, and HDAC6 and SIRT2 are its major deacetylases (Ishfaq et al 2012).…”

“…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). The results reported in this study are the first evidence that GC7 induces autophagy in 2fTGH cell line.…”

3q26‐29 Amplification in head and neck squamous cell carcinoma: a review of established and prospective oncogenes

“…Hypusination requires two sequentially acting enzymes, deoxyhypusine synthase and deoxyhypusine hydroxylase, and is essential for sustained proliferation in mammalian cells , potentially through enhanced translation of RhoA . Proliferative dependence on hypusination has been previously demonstrated in HSNCC .…”