miR-4652-3p suppresses glutamine metabolism induced by the inflammatory microenvironment in non-small cell lung cancer by regulating MYC/SLC1A5

TL;DR

This study shows that miR-4652-3p stops cancer cells from using glutamine for growth by targeting the MYC/SLC1A5 pathway in lung cancer.

Contribution

The novel finding is that miR-4652-3p suppresses glutamine metabolism in NSCLC by directly targeting both MYC and SLC1A5.

Findings

miR-4652-3p is downregulated in NSCLC, while MYC and SLC1A5 are upregulated.

miR-4652-3p inhibits glutamine metabolism and tumor progression in NSCLC by targeting the MYC/SLC1A5 axis.

Overexpression of MYC or SLC1A5 reverses the tumor-suppressive effects of miR-4652-3p.

Abstract

MicroRNAs (miRNAs) play a crucial role in tumorigenesis and malignant transformation. Studies indicate that miR-4652-3p is aberrantly expressed in various cancer types. However, its impact and underlying mechanisms in non-small cell lung cancer (NSCLC) have not been investigated.

A549 cells were stimulated with IL-1β, TNF-α, and IL-6 (each at 10 ng/ml) to mimic an inflammatory microenvironment. Metabolic status was evaluated by measuring glutamine uptake, α-ketoglutarate (α-KG), and ATP levels. Functional studies employed the glutaminase inhibitor (CB-839), the MYC inhibitor (10058-F4), SLC1A5 small interfering RNA (siSLC1A5-2), a miR-4652-3p mimic, and overexpression plasmids. Molecular interactions were validated using chromatin immunoprecipitation (ChIP), dual-luciferase reporter assays, and RNA pull-down experiment. CCK-8 and Transwell assays were used for the assessment of cell malignant phenotypes. The functional significance of miR-4652-3p was further verified in a xenograft mouse model.

miR-4652-3p was downregulated in NSCLC, while MYC and SLC1A5 were upregulated. Inflammatory stimulation enhanced A549 cell proliferation, glutamine uptake, and α-KG/ATP production; these effects were attenuated by CB-839. ChIP and dual-luciferase assays demonstrated that MYC binds the SLC1A5 promoter and activates its transcription. Inhibiting MYC or knocking down SLC1A5 significantly reduced glutamine uptake. Mechanistic analysis revealed that miR-4652-3p directly targets both MYC and SLC1A5 mRNA. miR-4652-3p suppressed glutamine metabolism in NSCLC cells by negatively regulating the MYC/SLC1A5 axis, consequently inhibiting cell growth and tumor progression in a xenograft mouse model, an effect reversed by MYC or SLC1A5 overexpression.

miR-4652-3p blocked the inflammatory microenvironment-induced glutamine metabolic reprogramming by directly suppressing the MYC/SLC1A5 axis, thereby inhibiting NSCLC progression. The miR-4652-3p/MYC/SLC1A5 pathway represents a key regulatory mechanism for metabolic adaptation in NSCLC.

The online version contains supplementary material available at 10.1186/s41065-026-00649-y.

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