Polyamines are naturally occurring molecules that are present in all living cells. They play important roles in fundamental biological functions such as cell growth and differentiation. In recent years, scientists have focused on these compounds, particularly spermidine, for their potential to support healthy aging. Often referred to as “Jello protectors,” they have been shown to stimulate autophagy, a cellular recycling process that removes damaged components. This advantage relies heavily on a protein called eukaryotic translation initiation factor 5A (eIF5A1).
At the same time, researchers have repeatedly observed high levels of polyamines in many types of cancer, and polyamines are associated with progressive tumor growth. This contrast created a scientific puzzle. How can the same molecules that seem to promote longevity also be linked to cancer?
Molecular puzzle of cancer metabolism
Although the association between polyamines and cancer has been recognized for many years, the detailed mechanisms behind the role of polyamines in tumor progression remain unclear. Cancer cells are known to have altered metabolism and rely heavily on aerobic glycolysis to rapidly generate energy. However, exactly how polyamines influence this metabolic shift is not fully understood.
To complicate matters further, eIF5A1 has a well-established function in normal, healthy cells. A closely related protein, eIF5A2, which shares 84% of its amino acid sequence, is associated with cancer development. A big unanswered question is why two nearly identical proteins behave so differently.
Large-scale proteomic analysis reveals distinct pathways
To investigate this, a team led by Associate Professor Tokyo Taira from the Faculty of Pharmaceutical Sciences, Tokyo University of Science, Japan, conducted a detailed study using advanced molecular and proteomic methods. Their results were published in the journal Volume 301, Issue 8. biochemistry journal. The findings reveal how polyamines stimulate cancer cell proliferation through biological pathways distinct from those involved in healthy aging.
Researchers worked with human cancer cell lines to investigate how polyamines affect protein production and metabolism. They first used drugs to lower polyamine levels, then added spermidine to restore them. This approach allows us to directly measure the effects of polyamines on cancer cells. Using high-resolution proteomics techniques, they analyzed changes across more than 6,700 proteins.
Their results showed that polyamines primarily promote glycolysis, a process that quickly converts glucose into energy, rather than promoting mitochondrial respiration, which is closely associated with healthy aging. The research team also found that polyamines increased levels of eIF5A2 and five ribosomal proteins, including RPS 27A, RPL36AL, and RPL22L1, all of which are associated with cancer severity.
eIF5A1 and eIF5A2 in normal and cancer cells
A side-by-side comparison of eIF5A1 and eIF5A2 provided important insights. “The biological activity of polyamines mediated by eIF5A differs between normal and cancer tissues,” explains Dr. Higashi. “In normal tissues, eIF5A1, which is activated by polyamines, activates mitochondria through autophagy, whereas in cancer tissues, eIF5A2, whose synthesis is promoted by polyamines, controls gene expression at the translational level and promotes cancer cell proliferation.”
In other words, polyamines cause very different effects depending on which protein they affect. In healthy cells, it supports cellular maintenance and energy production. In cancer cells, they help promote rapid proliferation.
How polyamines increase eIF5A2
Further experiments revealed how polyamines increase eIF5A2 levels. Under typical conditions, eIF5A2 protein production is suppressed by a small regulatory RNA molecule called miR-6514-5p. Researchers discovered that polyamines disrupt this natural brake, allowing eIF5A2 to be produced in large quantities. They also showed that eIF5A2 regulates a different group of proteins compared to eIF5A1, reinforcing the idea that these two similar proteins perform separate functions.
Implications for cancer treatment and supplement safety
These findings have important implications for both cancer treatment and the use of polyamine supplements. This result highlighted how important the biological context is. In healthy tissues, polyamines may provide anti-aging benefits through eIF5A1. In tissues that are cancerous or at risk of malignant transformation, the same molecule can stimulate tumor growth through eIF5A2. This dual behavior helps explain why polyamines are so difficult to interpret in medical research.
The study also identified promising new therapeutic targets. “Our findings reveal that eIF5A2, which is regulated by polyamines and miR-6514-5p, plays an important role in cancer cell proliferation and suggest that the interaction between eIF5A2 and ribosomes, which regulates cancer progression, is a selective target for cancer therapy,” said Dr. Higashi. Specifically targeting eIF5A2 could theoretically slow cancer growth without interfering with the beneficial effects associated with eIF5A1.
Overall, this study represents a major advance in understanding the complex and sometimes contradictory roles of polyamines. In the future, scientists may be able to design strategies that maintain the positive effects on healthy aging while reducing the likelihood of promoting the development of cancer.
This research was partially supported by Grants-in-Aid for Scientific Research (C) (number 18K06652) from the Japan Society for the Promotion of Science and the Hamaguchi Biochemical Foundation, as well as the Kanazawa University Cancer Research Institute’s Extramural Collaborative Research Grant.
