Journal Article

RNA-mediated inhibition of mitochondrial SHMT2 impairs cancer cell proliferation

Macone, Alberto, Riva, Agnese, Di Fonzo, Federica, Di Russo, Sara, Paiardini, Alessandro, Liberati, Francesca Romana, Contestabile, Roberto, Borsatti, Giulia Elizabeth, Arese, Marzia, Rinaldo, Serena, Spizzichino, Sharon, Boumis, Giovanna, Boi, Dalila, Giardina, Giorgio, Cutruzzolà, Francesca, Bouzidi, Amani, Guarguaglini, Giulia, Scribani Rossi, Chiara, Tramonti, Angela, Magnifico, Maria Chiara, Paone, Alessio

2025

Overview

Targeting metabolic reprogramming is crucial for cancer treatment. Recent advances highlight RNA’s ability to directly regulate enzyme activity through riboregulation. In this study, we used an RNA-based approach to inhibit the mitochondrial enzyme Serine hydroxymethyltransferase 2 (SHMT2), which lacks a selective in vivo inhibitor. SHMT2, often overexpressed in various cancers, is pivotal in one-carbon metabolism, a pathway vital for cell proliferation. Our results show that RNA effectively inhibits SHMT2’s serine-to-glycine conversion in vitro (IC 50  = 4.4 ± 0.2 nM). By using a mitochondrial import signal, we successfully delivered the inhibitory RNA into the mitochondria of lung cancer cells, reducing cell viability in vitro and tumor growth in vivo in a xenograft mouse model. These findings suggest that RNA-based strategies could be extended to selectively target other RNA-binding metabolic enzymes, offering potential solutions where small molecule inhibitors fall short or to counteract drug resistance.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
• Subject: 631/45/500 / 631/67/2327 / Apoptosis / Biochemistry / Biomedical and Life Sciences / Cancer therapies / Carbon / Cell Biology / Cell Cycle Analysis / Cell growth / Cell proliferation / Cell viability / Drug resistance / Enzymatic activity / Enzymes / Life Sciences / Lung cancer / Metabolism / Mitochondria / Ribonucleic acid / RNA / Serine / Stem Cells