Molecular targets of spermidine: implications for cancer suppression

Authors:

Andreas Zimmermann1-3, Sebastian J. Hofer1-3 and Frank Madeo1-3
PDF Download PubMed Link
Affiliations:

1 Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.

2 Field of Excellence BioHealth, University of Graz, Graz, Austria.

3 BioTechMed Graz, Graz, Austria.

Keywords: 

spermidine, cancer, molecular targets, immunosurveillance, hypusination, autophagy.

Abbreviatons:

DFMO – difluoromethylornithine;

eIF5A – eukaryotic translation initiation factor 5A;

FAO – fatty acid oxidation;

MTP – mitochondrial trifunctional protein;

NAFLD – non-alcoholic fatty liver disease;

NASH – non-alcoholic steatohepatitis;

NMDAR – neuronal glutamate-activated N-methyl-D-aspartate re-ceptor;

ODC – ornithine decarboxylase;

ROS – reactive oxygen species;

TAZ – transcriptional coactivator with PDZ-binding motif;

YAP – Yes-associated protein.

Corresponding Author(s):

Frank Madeo, Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria; frank.madeo@uni-graz.at

Conflict of interest statement:

F.M. is a scientific cofounder of Samsara Therapeutics, a company that develops novel pharmacological autophagy inducers. F.M. has equity interests in and is advisor of The Longevity Labs (TLL). S.J.H. and A.Z. declare no conflict of interest.

Please cite this article as:

Andreas Zimmermann, Sebastian J. Hofer and Frank Madeo (2023). Molecular targets of spermidine: implications for cancer suppression. Cell Stress 7(7): 50-58. doi: 10.15698/cst2023.07.281

© 2023 Zimmermann et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.

Abstract:

Spermidine is a ubiquitous, natural polyamine with geroprotective features. Supplementation of spermidine extends the lifespan of yeast, worms, flies, and mice, and dietary spermidine intake correlates with reduced human mortality. However, the crucial role of polyamines in cell proliferation has also implicated polyamine metabolism in neoplastic diseases, such as cancer. While depleting intracellular polyamine biosynthesis halts tumor growth in mouse models, lifelong external spermidine administration in mice does not increase cancer incidence. In contrast, a series of recent findings points to anti-neoplastic properties of spermidine administration in the context of immunotherapy. Various molecular mechanisms for the anti-aging and anti-cancer properties have been proposed, including the promotion of autophagy, enhanced translational control, and augmented mitochondrial function. For instance, spermidine allosterically activates mitochondrial trifunctional protein (MTP), a bipartite protein complex that mediates three of the four steps of mitochondrial fatty acid b-oxidation. Through this action, spermidine supplementation is able to restore MTP-mediated mitochondrial respiratory capacity in naïve CD8+ T cells to juvenile levels and thereby improves T cell activation in aged mice. Here, we put this finding into the context of the previously described molecular target space of spermidine.