UBA5 inhibition restricts lung adenocarcinoma via blocking macrophage M2 polarization and cisplatin resistance

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Ubiquitin-like modifier-activating enzyme 5 (UBA5) is implicated in cancer but its role in lung adenocarcinoma (LUAD) is unclear.
• UBA5 is involved in ufmylation and sumoylation pathways, making it a potential therapeutic target.

Purpose of the Study:

• To investigate the role of UBA5 in LUAD progression and its potential as a therapeutic target.
• To explore the impact of UBA5 on the tumor immune microenvironment and cisplatin resistance in LUAD.

Main Methods:

• Analysis of UBA5 expression in LUAD patient tissues and correlation with clinical stages (TNM).
• In vitro and in vivo experiments using pharmacological inhibition (DKM 2-93) and genetic knockdown (shRNA) of UBA5.
• Assessment of UBA5's effect on LUAD cell proliferation, M2 macrophage polarization, lactate production, and tumor heterogeneity.
• Evaluation of UBA5's influence on cisplatin resistance and the tumor immune microenvironment.

Main Results:

• UBA5 is upregulated in LUAD and correlates with advanced TNM stages and poor patient prognosis.
• Pharmacological inhibition and genetic knockdown of UBA5 significantly suppress LUAD cell growth in vitro and in vivo.
• High UBA5 expression promotes M2 macrophage infiltration, alters immune microenvironment components, and increases tumor heterogeneity.
• UBA5 overexpression confers cisplatin resistance, while UBA5 inhibition enhances sensitivity to cisplatin.

Conclusions:

• UBA5 plays a tumor-promoting role in LUAD by driving proliferation, M2 macrophage polarization, and cisplatin resistance.
• Targeting UBA5 represents a promising therapeutic strategy for LUAD, potentially overcoming resistance mechanisms.
• UBA5 modulation impacts the tumor immune microenvironment, suggesting broader therapeutic implications.