Mevalonate Metabolic Reprogramming Drives Cisplatin Resistance in Bladder Cancer: Mechanisms and Therapeutic...

Area of Science:

• Oncology
• Metabolic pathways
• Cancer research

Background:

• Mevalonate metabolism dysregulation is implicated in various cancers.
• Its specific role in bladder cancer (BCa) prognosis and treatment resistance is not well understood.

Purpose of the Study:

• To investigate the impact of mevalonate metabolism on bladder cancer patient outcomes.
• To determine its association with cisplatin chemosensitivity.
• To explore its potential as a therapeutic target.

Main Methods:

• Utilized transcriptomic and clinical data from TCGA and GEO databases.
• Employed Non-negative Matrix Factorization (NMF) for metabolic subtype classification.
• Analyzed associations with clinical features, immune infiltration, and cisplatin resistance using GSVA, Kaplan-Meier, and ssGSEA, alongside in vitro studies.

Main Results:

• Identified two metabolic subtypes (C1/C2), with C1 exhibiting higher mevalonate metabolism (MVAscore), poorer prognosis, and lower immune infiltration.
• Found a positive correlation between mevalonate metabolism and platinum resistance, evident in cisplatin-resistant cells.
• In vitro, simvastatin reduced bladder cancer cell proliferation and increased cisplatin sensitivity.

Conclusions:

• Mevalonate metabolism significantly influences bladder cancer heterogeneity, chemoresistance, and anti-tumor immunity.
• Its dysregulation serves as a prognostic biomarker and a viable therapeutic target.
• Targeting mevalonate metabolism with simvastatin enhances cisplatin efficacy, suggesting a personalized chemotherapy approach.