Review Article | Published:

Polyamine metabolism and cancer: treatments, challenges and opportunities

Nature Reviews Cancervolume 18pages681695 (2018) | Download Citation

Abstract

Advances in our understanding of the metabolism and molecular functions of polyamines and their alterations in cancer have led to resurgence in the interest of targeting polyamine metabolism as an anticancer strategy. Increasing knowledge of the interplay between polyamine metabolism and other cancer-driving pathways, including the PTEN–PI3K–mTOR complex 1 (mTORC1), WNT signalling and RAS pathways, suggests potential combination therapies that will have considerable clinical promise. Additionally, an expanding number of promising clinical trials with agents targeting polyamines for both therapy and prevention are ongoing. New insights into molecular mechanisms linking dysregulated polyamine catabolism and carcinogenesis suggest additional strategies that can be used for cancer prevention in at-risk individuals. In addition, polyamine blocking therapy, a strategy that combines the inhibition of polyamine biosynthesis with the simultaneous blockade of polyamine transport, can be more effective than therapies based on polyamine depletion alone and may involve an antitumour immune response. These findings open up new avenues of research into exploiting aberrant polyamine metabolism for anticancer therapy.

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Acknowledgements

Work in the Casero laboratory is supported by grants from the US National Institutes of Health (CA204345), the Maryland Cigarette Restitution Fund and the Samuel Waxman Cancer Research Foundation.

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Affiliations

  1. Department of Oncology, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA

    • Robert A. Casero Jr
    •  & Tracy Murray Stewart
  2. Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA, USA

    • Anthony E. Pegg

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Contributions

All authors researched data for the article, contributed to the discussion of content, wrote the article and reviewed and/or edited the manuscript before submission.

Competing interests

The authors receive US National Institutes of Health grant support (R.A.C.) and are patent holders (R.A.C. and A.E.P.). T.M.S. declares no competing interests.

Corresponding author

Correspondence to Robert A. Casero Jr.

Glossary terms

Cytostasis

The process by which cells stop dividing without dying; it is a common response by normal cells to polyamine depletion, which can then recover growth once the polyamine block is removed.

Hypusine

A unique amino acid found in all eukaryotes and some archaea that is the product of a post-translational modification of a specific lysine (K50 in humans) residue of the transcription factor eukaryotic initiation factor 5A isoform 1 (eIF5A), which is produced by the transfer of the aminobutyl moiety of spermidine to the lysine residue.

5′-methylthioadenosine phosphorylase

(MTAP). The enzyme that catalyses the initial step in methionine and adenosine nucleotide salvage from the methylthioadenosine product of both spermidine and spermine synthesis; the gene coding for this protein is frequently lost or silenced in tumours, thus facilitating a unique biochemical difference that may be exploited in many cancers.

Protonated

The state of having accepted a proton; in the case of polyamines at physiological pH, all imine and amine nitrogens are positively charged.

Proenzyme

The inactive precursor of an active enzyme; S‑adenosylmethionine decarboxylase (AdoMetDC) is a self-processing proenzyme that undergoes an autocatalytic serinolysis to produce the pyruvoyl group necessary for the activity of the mature AdoMetDC enzyme.

Ferroptosis

An iron-dependent programmed cell death process that is characterized by an accumulation of lipid peroxidases.

Prodrug

A formulation of an inactive compound that once metabolized or altered by the cellular environment produces the active form of the drug.

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https://doi.org/10.1038/s41568-018-0050-3