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Targeting the polyamine-hypusine circuit for the prevention and treatment of cancer

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Abstract

The unique amino acid hypusine is present in only two proteins in eukaryotic cells, eukaryotic translation initiation factor 5A-1 (eIF5A1), and eIF5A2, where it is covalently linked to the lysine-50 residue of these proteins via a post-translational modification coined hypusination. This unique modification is directed by two highly conserved and essential enzymes, deoxyhypusine synthase (DHPS), and deoxyhypusine hydroxylase (DOHH), which selectively use the polyamine spermidine as a substrate to generate hypusinated eIF5A. Notably, elevated levels of polyamines are a hallmark of most tumor types, and increased levels of polyamines can also be detected in the urine and blood of cancer patients. Further, in-clinic agents that block the function of key biosynthetic enzymes in the polyamine pathway markedly impair tumor progression and maintenance of the malignant state. Thus, the polyamine pathway is attractive as a prognostic, prevention and therapeutic target. As we review, recent advances in our understanding of the specific functions of hypusinated eIF5A and its role in tumorigenesis suggest that the polyamine-hypusine circuit is a high priority target for cancer therapeutics.

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Abbreviations

eIF5A:

Eukaryotic translation initiation factor 5A

DHPS:

Deoxyhypusine synthase

DOHH:

Deoxyhypusine hydroxylase

GC7:

N1-guanyl-1,7-diamineheptane

CPX:

Ciclopirox

DEF:

Deferiprone

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Acknowledgments

This study was supported by the NCI Comprehensive Cancer Center Grant P30-CA076292 to the H. Lee Moffitt Cancer Center and Research Institute.

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  1. Department of Tumor Biology, The Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA

    Shima Nakanishi & John L. Cleveland

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  1. Shima Nakanishi
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  2. John L. Cleveland
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Correspondence to John L. Cleveland.

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Nakanishi, S., Cleveland, J.L. Targeting the polyamine-hypusine circuit for the prevention and treatment of cancer. Amino Acids 48, 2353–2362 (2016). https://doi.org/10.1007/s00726-016-2275-3

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