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

IF 1.1 4区生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Protein and Peptide Letters Pub Date : 2025-09-03 DOI:10.2174/0109298665403178250806111943

Qixiang Fang, Chengyu You, Xi Xiao, Yang Liu, Weiguang Yang, Qingchao Li, Liangliang Qing, Zhilong Dong

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引用次数: 0

Abstract

Introduction: Dysregulation of mevalonate metabolism is a hallmark of tumorigenesis and therapy resistance across malignancies, though its role in bladder cancer remains unclear. This study aimed to elucidate its impact on prognosis and cisplatin chemosensitivity in bladder cancer.

Methods: Transcriptomic data and clinical information of bladder cancer patients were obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Non-negative matrix factorization (NMF) was used to cluster mevalonate metabolism-related genes into distinct metabolic subtypes (C1 and C2). Associations between mevalonate metabolism, clinical characteristics, immune infiltration, and cisplatin resistance were analyzed using Gene Set Variation Analysis (GSVA), Kaplan-Meier survival analysis, single-sample Gene Set Enrichment Analysis (ssGSEA), and in vitro experiments.

Results: NMF clustering classified bladder cancer patients into two metabolic subtypes (C1/C2). The C1, characterized by higher mevalonate metabolism (MVAscore), was associated with a poorer prognosis, shorter overall survival (OS), and higher T-stage and pathological grades. Immune analysis showed lower immune cell infiltration in C1. Immune infiltration analysis revealed significantly lower immune infiltration levels in the C1. Further analysis revealed a positive correlation between mevalonate metabolism and platinum resistance, with a notable increase in mevalonate metabolism observed in cisplatin-resistant bladder cancer cells. In vitro, simvastatin inhibited the proliferation of bladder cancer cells and enhanced their sensitivity to cisplatin.

Discussion: Mevalonate metabolism drives BCa heterogeneity and chemoresistance while suppressing anti-tumor immunity. Its dysregulation serves as both a prognostic biomarker and a target for therapeutic intervention.

Conclusion: Mevalonate metabolism contributes to cisplatin resistance in bladder cancer and represents a potential therapeutic target. Simvastatin targeting this pathway enhances the efficacy of cisplatin, providing a novel personalized chemotherapy strategy.

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甲羟丙酸代谢重编程驱动膀胱癌顺铂耐药：机制和治疗靶向。

甲羟戊酸代谢失调是恶性肿瘤发生和治疗耐药的标志，尽管其在膀胱癌中的作用尚不清楚。本研究旨在阐明其对膀胱癌患者预后及顺铂化疗敏感性的影响。方法：从cancer Genome Atlas （TCGA）和Gene Expression Omnibus （GEO）数据库中获取膀胱癌患者的转录组学数据和临床信息。采用非负矩阵分解法（NMF）将甲羟戊酸代谢相关基因聚类为不同的代谢亚型（C1和C2）。采用基因集变异分析（GSVA）、Kaplan-Meier生存分析、单样本基因集富集分析（ssGSEA）和体外实验分析甲羟戊酸代谢、临床特征、免疫浸润和顺铂耐药之间的关系。结果：NMF聚类将膀胱癌患者分为两个代谢亚型（C1/C2）。以高甲羟戊酸代谢（MVAscore）为特征的C1与较差的预后、较短的总生存期（OS）、较高的t分期和病理分级相关。免疫分析显示C1的免疫细胞浸润较低。免疫浸润分析显示C1区免疫浸润水平明显降低。进一步分析显示甲羟戊酸代谢与铂耐药呈正相关，在顺铂耐药膀胱癌细胞中观察到甲羟戊酸代谢显著增加。在体外实验中，辛伐他汀抑制膀胱癌细胞的增殖，增强其对顺铂的敏感性。讨论：甲羟戊酸代谢驱动BCa异质性和化疗耐药，同时抑制抗肿瘤免疫。它的失调既是预后生物标志物，也是治疗干预的目标。结论：甲羟戊酸代谢与膀胱癌顺铂耐药有关，是一个潜在的治疗靶点。辛伐他汀靶向这一途径，提高了顺铂的疗效，提供了一种新的个性化化疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Protein and Peptide Letters 生物-生化与分子生物学

CiteScore

2.90

自引率

0.00%

发文量

审稿时长

2 months

期刊介绍： Protein & Peptide Letters publishes letters, original research papers, mini-reviews and guest edited issues in all important aspects of protein and peptide research, including structural studies, advances in recombinant expression, function, synthesis, enzymology, immunology, molecular modeling, and drug design. Manuscripts must have a significant element of novelty, timeliness and urgency that merit rapid publication. Reports of crystallization and preliminary structure determination of biologically important proteins are considered only if they include significant new approaches or deal with proteins of immediate importance, and preliminary structure determinations of biologically important proteins. Purely theoretical/review papers should provide new insight into the principles of protein/peptide structure and function. Manuscripts describing computational work should include some experimental data to provide confirmation of the results of calculations. Protein & Peptide Letters focuses on: Structure Studies Advances in Recombinant Expression Drug Design Chemical Synthesis Function Pharmacology Enzymology Conformational Analysis Immunology Biotechnology Protein Engineering Protein Folding Sequencing Molecular Recognition Purification and Analysis