Tokyo, Japan — August 1, 2025 — Polyamines, naturally occurring molecules essential for cell growth and differentiation, have long fascinated scientists for their ability to extend lifespan and support healthy aging. Yet, these same compounds—particularly spermidine—are also linked to cancer development and rapid tumor growth. A new study led by Associate Professor Kyohei Higashi at Tokyo University of Science has now unraveled the molecular mechanisms behind this paradox, offering fresh insights into both aging research and cancer therapy.

The findings were first made available online on July 3, 2025, and formally published in The Journal of Biological Chemistry (Volume 301, Issue 8) on August 1, 2025.

Polyamines: A Biological Paradox

Polyamines are known to activate autophagy, a cellular recycling process that supports longevity, largely through the protein eIF5A1. However, elevated levels of polyamines are consistently observed in cancer, where they appear to drive tumor progression.

A long-standing puzzle in biomedical science has been why these same molecules can both extend lifespan and fuel malignancy. One possible answer lies in two closely related proteins: eIF5A1 and eIF5A2. While they share 84% of their amino acid sequence, their biological effects diverge sharply.

New Insights from Proteomic Analysis

To investigate, Dr. Higashi’s team used human cancer cell lines and manipulated polyamine levels by first depleting them with drugs and then restoring them with spermidine supplementation. Using advanced proteomic techniques, the team analyzed changes in more than 6,700 proteins.

The results showed that in cancer cells, polyamines strongly stimulate glycolysis, the rapid breakdown of glucose for energy, rather than the mitochondrial respiration linked to healthy aging. Additionally, polyamines increased the expression of eIF5A2 and several ribosomal proteins (including RPS27A, RPL36AL, and RPL22L1), all of which are associated with cancer progression.

eIF5A1 vs. eIF5A2: A Tale of Two Proteins

A direct comparison of the two proteins revealed why polyamines play such different roles in health versus cancer.

“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.”

The study further revealed that polyamines interfere with miR-6514-5p, a regulatory RNA that normally suppresses eIF5A2 production. By lifting this suppression, polyamines enable elevated eIF5A2 expression, which in turn regulates an entirely different protein network than eIF5A1.

Implications for Cancer Therapy and Healthy Aging

These discoveries underscore the context-dependent nature of polyamines. While beneficial in promoting longevity through eIF5A1, they can be harmful in malignant environments by stimulating eIF5A2-driven cancer pathways.

Importantly, this mechanism highlights a new therapeutic opportunity.

“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.

Future therapies could selectively block eIF5A2 activity in cancer without interfering with the beneficial effects of eIF5A1, opening the door to more precise treatments.

About the Tokyo University of Science

Founded in 1881, Tokyo University of Science (TUS) is Japan’s largest private science-specialized research university, with campuses in Tokyo and Hokkaido. With a mission of “Creating science and technology for the harmonious development of nature, human beings, and society,” TUS advances cutting-edge research across diverse scientific disciplines. It is the only private university in Asia to have produced Nobel Prize winners in the natural sciences.

About Dr. Kyohei Higashi

Dr. Kyohei Higashi is an Associate Professor in the Faculty of Pharmaceutical Sciences at TUS. He earned his Ph.D. in Pharmaceutical Sciences from Chiba University and has authored over 90 research articles. His research focuses on clinical and analytical biochemistry, with a special interest in physical pharmacy. He has received multiple awards, including the Carbohydrate Research JSCR42 Poster Award (2023), and is an active member of several academic societies, including FCCA (Trends in Glycoscience and Glycotechnology).

Key Highlights

• Polyamines extend lifespan via eIF5A1 but promote cancer through eIF5A2.
  
• In cancer cells, polyamines enhance glycolysis and ribosomal protein expression linked to malignancy.
• Polyamines disable miR-6514-5p suppression, allowing harmful eIF5A2 accumulation.
• Targeting eIF5A2–ribosome interactions could provide a new therapeutic strategy for cancer.
• Findings clarify why polyamines have paradoxical effects, guiding safer use in anti-aging research.
  

Original Publication
Authors: Masato Suzuki, Takehiro Suzuki, Yoshio Nakano, Ken Matsumoto, Hitomi Manaka, Masahiro Komeno, Shoma Tamori, Akira Sato, Naoshi Dohmae, Kazunori Akimoto, Satoru Miyazaki, Takashi Suda, Toshihiko Toida, Keiko Kashiwagi, Kazuei Igarashi and Kyohei Higashi.
Journal: Journal of Biological Chemistry
DOI: 10.1016/j.jbc.2025.110453
Method of Research: Experimental study
Subject of Research: Cells
Article Title: Polyamines stimulate the protein synthesis of the initiation factor eIF5A2 participating in mRNA decoding distinct from eIF5A1
Article Publication Date: 1-Aug-2025
COI Statement: The authors declare that they have no conflicts of interest with the contents of this article.

Original Source: https://www.tus.ac.jp/en/mediarelations/archive/20250827_8803.html

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