Polyamines are naturally produced molecules present in all living cells. They play a vital role in basic biological functions, including cell growth and specialization. In recent years, scientists have focused on these compounds, especially spermidine, for their potential to support healthy aging. Often described as ‘geroprotectors,’ they have been shown to stimulate autophagy, a cellular recycling process that clears out damaged components. This benefit largely depends 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, where they are linked to aggressive tumor growth. This contrast has created a scientific puzzle. How can the same molecules that appear to promote longevity also be associated with cancer?
A Molecular Puzzle in Cancer Metabolism
Although the connection between polyamines and cancer has been recognized for years, the detailed mechanisms behind their role in tumor progression have remained unclear. Cancer cells are known to alter their metabolism, relying heavily on aerobic glycolysis to rapidly generate energy. However, exactly how polyamines influence this metabolic shift has not been fully understood.
Adding to the complexity, eIF5A1 has well established functions in normal, healthy cells. A closely related protein, eIF5A2, shares 84% of its amino acid sequence but has been linked to cancer development. Why two nearly identical proteins behave so differently has been a major unanswered question.
Large Scale Proteomic Analysis Reveals Distinct Pathways
To investigate, a team led by Associate Professor Kyohei Higashi from the Faculty of Pharmaceutical Sciences at Tokyo University of Science in Japan carried out an in-depth study using advanced molecular and proteomic methods. Their results were published in Volume 301, Issue 8 of the Journal of Biological Chemistry. The findings clarify how polyamines stimulate cancer cell growth through biological routes that differ from those involved in healthy aging.
The researchers worked with human cancer cell lines to examine how polyamines affect protein production and metabolism. They first reduced polyamine levels using a drug, then restored them by adding spermidine. This approach allowed them to directly measure the impact of polyamines on cancer cells. Using high-resolution proteomic techniques, they analyzed changes across more than 6,700 proteins.
Their results showed that polyamines primarily boost glycolysis, the process that quickly converts glucose into energy, rather than enhancing mitochondrial respiration, which is more closely tied to healthy aging. The team also found that polyamines increase levels of eIF5A2 and five ribosomal proteins, including RPS 27A, RPL36AL, and RPL22L1, all of which are associated with cancer severity.
eIF5A1 vs eIF5A2 in Normal and Cancer Cells
A side by side comparison of eIF5A1 and eIF5A2 provided critical insight. “The biological activity of polyamines via eIF5A differs between normal and cancer tissues,” explains Dr. Higashi. “In normal tissues, eIF5A1, activated by polyamines, activates mitochondria via autophagy, whereas in cancer tissues, eIF5A2, whose synthesis is promoted by polyamines, controls gene expression at the translational level to facilitate the proliferation of cancer cells.”
In other words, polyamines trigger very different effects depending on which protein they influence. In healthy cells, they support cellular maintenance and energy production. In cancer cells, they help drive rapid growth.
How Polyamines Increase eIF5A2
Further experiments uncovered how polyamines raise eIF5A2 levels. Under typical conditions, production of the eIF5A2 protein is restrained by a small regulatory RNA molecule called miR-6514-5p. The researchers found that polyamines disrupt this natural brake, allowing eIF5A2 to be produced in greater amounts. They also showed that eIF5A2 controls a distinct group of proteins compared to eIF5A1, reinforcing the idea that these two similar proteins carry out separate functions.
Implications for Cancer Therapy and Supplement Safety
These findings carry important implications for both cancer treatment and the use of polyamine supplements. The results highlight how strongly biological context matters. In healthy tissues, polyamines may provide anti-aging benefits through eIF5A1. In tissues that are cancerous or at risk of becoming malignant, the same molecules can stimulate tumor growth through eIF5A2. This dual behavior helps explain why polyamines have been so challenging to interpret in medical research.
The study also identifies a promising new therapeutic target. “Our findings reveal an important role for eIF5A2, regulated by polyamines and miR-6514-5p, in cancer cell proliferation, suggesting that the interaction between eIF5A2 and ribosomes, which regulates cancer progression, is a selective target for cancer treatment,” remarks Dr. Higashi. Targeting eIF5A2 specifically could, in theory, slow cancer growth without interfering with the beneficial effects linked to eIF5A1.
Overall, this research marks a significant advance in understanding the complex and sometimes contradictory roles of polyamines. In the future, scientists may be able to design strategies that preserve their positive effects on healthy aging while reducing their potential to support cancer development.
This study was supported in part by a Grant-in-Aid for Scientific Research (C) (No. 18K06652) from the Japan Society for the Promotion of Science, the Hamaguchi Foundation for the Advancement of Biochemistry, and an Extramural Collaborative Research Grant of the Cancer Research Institute, Kanazawa University, Japan.
