Polyamines: their significance for maintaining health and contributing to diseases

Abstract

Polyamines are essential for the growth and proliferation of mammalian cells and are intimately involved in biological mechanisms such as DNA replication, RNA transcription, protein synthesis, and post-translational modification. These mechanisms regulate cellular proliferation, differentiation, programmed cell death, and the formation of tumors. Several studies have confirmed the positive effect of polyamines on the maintenance of health, while others have demonstrated that their activity may promote the occurrence and progression of diseases. This review examines a variety of topics, such as polyamine source and metabolism, including metabolism, transport, and the potential impact of polyamines on health and disease. In addition, a brief summary of the effects of oncogenes and signaling pathways on tumor polyamine metabolism is provided. Video Abstract.

Keywords: Cancer; Disease; Mechanism; Oncogene; Polyamine metabolism.

Fig. 1

The source and metabolism of polyamine. a The presence of polyamines is ubiquitous in virtually all food sources. The main polyamines in breast milk are spermidine and spermidine, and the content and distribution of polyamines in plant-derived and animal-derived foods differ based on their respective categorizations. b The intestinal microbiota has the capability to produce polyamines. c The biosynthesis of polyamines commences with the conversion of L-ornithine into putrescine via the action of ornithine decarboxylase (ODC). Subsequently, the addition of an aminopropyl group, which is contributed by dcAdoMet, results in the formation of spermidine and spermine. In the process of polyamine catabolism, the enzyme SSAT are responsible for the acetylation of spermine and spermidine, resulting in the production of N1-acetylspermine and N1-acetylspermidine. SMOX can oxidize spermine directly to spermidine These metabolites are either secreted from cells or undergo reconversion back into spermidine and putrescine via the enzyme PAOX. Created with BioRender.com

Fig. 2

Cardiovascular protective effect of polyamines. (I) Spd effectively reinstates the NO-mediated endothelium-dependent dilation (EDD) by augmenting the level of NO bioavailability and abating oxidative stress, therefore reducing blood pressure. (II). Spd increases autophagy flux through the AMPK-mTOR signaling pathway, contributing to the stimulation of cardiomyocyte protective autophagy. (III). The structure and function of cardiomyocytes can be improved through Titin phosphorylation and mitochondria formation. And Spd can activate mitochondrial biogenesis through SIRT1-mediated PGC-1α deacetylation. (IV). Spd effectively suppresses the release of TNF-α by immune cells, consequently lowering levels of subclinical chronic inflammation and ultimately preventing the onset of myocardial injury. Created with BioRender.com

Fig. 3

The regulatory pathways of polyamines in CRC. a Activation of the Wnt signaling pathway results in the inability of β-catenin to undergo phosphorylation by GSK-3β, ultimately leading to its accumulation within the cell and subsequent nuclear translocation. Upon entering the nucleus, MYC expression is upregulated through binding to TCF/LEF, which will increase the expression of ODC. B Excessive stimulation of the RAS signaling pathway results in the stimulation of ODC expression while suppressing the expression of SSAT. c. PI3K/AKT pathway can regulat the Wnt and Ras signaling pathways. Elevating the expression of ODC and reducing the expression of SSAT will result in an augmented intracellular pool of polyamines. The elevation in polyamine concentration frequently correlates with an unfavorable prognosis. Created with BioRender.com

Fig. 4

Regulation of polyamine by oncogenes and signaling pathways. a The translation product of TP53, known as p53, regulates the expression of ODC, a key enzyme in polyamine synthesis. Mutations in the TP53 gene will have a significant impact on the metabolism and function of polyamines. The tumor suppressor gene TP53 can be inactivated in four ways: Missense mutation; Truncating mutation; Frameshift mutation; Splice mutation. b Activated MYC exerts regulatory effects on several crucial enzymes involved in polyamine metabolism, including ODC, SRM and SMS. Genetic aberrations, transcriptional regulation, and protein instability can activate MYC. Increasing phospho-serine 62 (P-S62)-MYC and decreasing phospho-threonine 58 (P-T58)-MYC stabilize MYC protein. c. RAS-RAF-MEK-ERK signaling pathway upregulates the expression of ODC and downregulates the expression of SSAT. d PI3K-mTORC1 signaling pathway increases the expression of dcAdoMet, thus regulating the biosynthesis of polyamine. Created with BioRender.com