RNA-mediated inhibition of mitochondrial SHMT2 impairs cancer cell proliferation

TL;DR

This study shows that RNA can be used to inhibit a key cancer-related enzyme in mitochondria, reducing cancer cell growth in lab and animal models.

Contribution

The paper introduces an RNA-based method to selectively inhibit SHMT2, a mitochondrial enzyme with no existing selective inhibitor.

Findings

RNA inhibited SHMT2's activity in vitro with an IC50 of 4.4 ± 0.2 nM.

Mitochondrial delivery of the RNA reduced lung cancer cell viability and tumor growth in mice.

RNA-based strategies may target other RNA-binding metabolic enzymes where traditional inhibitors fail.

Abstract

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 (IC50 = 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.

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