Cancer etiology is influenced by alterations in
protein synthesis that are not fully understood. In this study, we took a novel approach to investigate the role of the eukaryotic translation
initiation factor eIF5A in human
cervical cancers, where it is widely overexpressed. eIF5A contains the distinctive
amino acid hypusine, which is formed by a posttranslational modification event requiring
deoxyhypusine hydroxylase (DOHH), an
enzyme that can be inhibited by the drugs
ciclopirox and
deferiprone. We found that proliferation of
cervical cancer cells can be blocked by DOHH inhibition with either of these pharmacologic agents, as well as by RNA interference-mediated silencing of eIF5A, DOHH, or another
enzyme in the
hypusine pathway. Proteomic and
RNA analyses in HeLa
cervical cancer cells identified two groups of
proteins in addition to eIF5A that were coordinately affected by
ciclopirox and
deferiprone. Group 1
proteins (Hsp27, NM23, and DJ-1) were downregulated at the translational level, whereas group 2
proteins (TrpRS and PRDX2) were upregulated at the
mRNA level. Further investigations confirmed that eIF5A and DOHH are required for Hsp27 expression in
cervical cancer cells and for regulation of its key target IκB and hence NF-κB. Our results argue that mature eIF5A controls a translational network of
cancer-driving genes, termed the eIF5A regulon, at the levels of
mRNA abundance and translation. In coordinating cell proliferation, the eIF5A regulon can be modulated by drugs such as
ciclopirox or
deferiprone, which might be repositioned to control
cancer cell growth.