Polyamines have become familiar players in longevity research, with spermidine in particular attracting attention for its ability to stimulate autophagy and support mitochondrial function. But a new study shows that the same molecules can also drive cancer cell growth – through a distinct pathway centered on the translation factor eIF5A2.
Researchers at Tokyo University of Science set out to resolve this apparent contradiction using HeLa and breast cancer cell lines, combining polyamine depletion and rescue experiments with large-scale proteomics, transcriptomics, Western blotting, qPCR, and metabolic flux analysis. After treating cells with the ornithine decarboxylase inhibitor DFMO and then restoring spermidine, they tracked changes across more than 6,700 proteins by nano LC-MS/MS. Their results pointed not to healthier mitochondrial metabolism, but to enhanced glycolysis: polyamines increased expression of proteins linked to cancer-associated glucose metabolism, including PDK1 and PKM2, while extracellular acidification and oxygen-consumption assays showed a stronger effect on glycolytic activity than on mitochondrial respiration.
The key mechanistic finding was a divergence between the closely related proteins eIF5A1 and eIF5A2. “The biological activity of polyamines via eIF5A differs between normal and cancer tissues,” said co-author Kyohei Higashi in a press release. “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 team showed that polyamines boost eIF5A2 at the translational level by interfering with the suppressive action of miR-6514-5p at the 5′ untranslated region of eIF5A2 mRNA. Silencing eIF5A2 inhibited proliferation more strongly than silencing eIF5A1 in cervical and breast cancer cell lines, while proteomic profiling suggested that the two proteins regulate different subsets of targets. Polyamines also increased several ribosomal proteins associated with malignancy, including RPS27A, RPL36A/L, and RPL22L1.
“Our findings reveal an important role for eIF5A2, regulated by polyamines and miR-6514-5p, in cancer cell proliferation,” Higashi said, adding that the interaction between eIF5A2 and ribosomes could offer “a selective target for cancer treatment.”
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