Increasing cisplatin exposure promotes small-cell lung cancer transformation after a shift from glucose metabolism to fatty acid metabolism.

IF 2.7 3区 医学 Q3 ONCOLOGY
Qiu-Yu Zhao, Wen-Jun Liu, Jian-Guang Wang, He Li, Jia-Lu Lv, Yumeng Wang, Chun Wang
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引用次数: 0

Abstract

Objectives: Lung cancer is a leading cause of global cancer mortality. Clinical observations reveal that histological transformation from non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is accompanied by mutations in TP53 and RB1. By applying gradually increasing cisplatin concentrations to mimic the escalating drug pressure within the tumor microenvironment, this study investigated the link between phenotypic transformation to SCLC in cisplatin-resistant human lung adenocarcinoma cells and alterations in cellular energy production pathways.

Materials and methods: We established two cisplatin-resistant NSCLC cell lines with varying resistance levels. RNAseq analyses identified TP53 and RB1 gene mutations. Comprehensive functional assays were performed to characterize A549/DDP1 μg/mL and A549/DDP3 μg/mL cells, focusing on proliferation and migratory capabilities. Cellular bioenergetics were assessed through glycolysis and oxidative phosphorylation analyses. Western blotting was employed to examine epithelial-mesenchymal transition (EMT), glucose metabolism, and lipid metabolism markers. Cell cycle distribution was analyzed by flow cytometry. Additionally, a xenograft mouse model was developed for in vivo validation.

Results: TP53 and RB1 mutations were associated with cisplatin concentration-dependent phenotypic transformation, with A549/DDP cells acquiring a more aggressive SCLC-like phenotype (In the article we call the A549/DDPSCLC cells). Analysis of cell bioenergetics profiling and Western blot analyses revealed enhanced glucose metabolism in A549/DDP1 μg/mL cells, while A549/DDPSCLC cells exhibited predominant lipid metabolism. Compound3K and Etomoxir specifically inhibit the activity of PKM2 and CPT1A, respectively, with Etomoxir demonstrating substantially inhibited A549/DDPSCLC cells growth and more cell cycle arrest in the G0/G1 phase. Combinatorial of Compound3K and Etomoxir effectively induced cell death in A549/DDPSCLC phenotype cells in vitro. Etomoxir alone or combined with Compound3K significantly inhibited tumor growth in vivo, with enhanced efficacy in the combination group.

Conclusions: This study provides the first evidence of cisplatin concentration-dependent metabolic reprogramming during NSCLC-to-SCLC transformation. We identified a phenotypic transition from NSCLC to SCLC accompanied by a metabolic shift from glucose to fatty acid metabolism, offering new insights into therapeutic strategies for treatmentresistant lung cancer.

增加顺铂暴露可促进小细胞肺癌从葡萄糖代谢向脂肪酸代谢转变。
目的:肺癌是全球癌症死亡的主要原因。临床观察发现,从非小细胞肺癌(NSCLC)到小细胞肺癌(SCLC)的组织学转变伴随着TP53和RB1的突变。本研究通过使用逐渐增加的顺铂浓度来模拟肿瘤微环境中不断升高的药物压力,研究了顺铂耐药人肺腺癌细胞表型转化为SCLC与细胞能量产生途径改变之间的联系。材料和方法:我们建立了两种不同耐药水平的顺铂耐药NSCLC细胞系。RNAseq分析发现TP53和RB1基因突变。对A549/DDP1 μg/mL和A549/DDP3 μg/mL细胞进行综合功能检测,重点关注细胞的增殖和迁移能力。细胞生物能量学通过糖酵解和氧化磷酸化分析进行评估。Western blotting检测上皮-间质转化(epithelial-mesenchymal transition, EMT)、葡萄糖代谢和脂质代谢标志物。流式细胞术分析细胞周期分布。此外,还建立了异种移植小鼠模型进行体内验证。结果:TP53和RB1突变与顺铂浓度依赖性表型转化相关,A549/DDP细胞获得更具侵袭性的sclc样表型(在文章中我们称之为A549/DDPSCLC细胞)。细胞生物能量学分析和Western blot分析显示,A549/DDP1 μg/mL细胞的糖代谢增强,而A549/DDPSCLC细胞以脂质代谢为主。化合物3k和依托莫西分别特异性抑制PKM2和CPT1A的活性,其中依托莫西显示出显著抑制A549/DDPSCLC细胞生长和更多的细胞周期阻滞在G0/G1期。复方3k联合依托莫西可有效诱导体外A549/DDPSCLC表型细胞死亡。在体内,依托莫西单用或联用Compound3K均能显著抑制肿瘤生长,且联用组疗效增强。结论:本研究首次提供了nsclc向sclc转化过程中顺铂浓度依赖性代谢重编程的证据。我们发现从NSCLC到SCLC的表型转变伴随着从葡萄糖代谢到脂肪酸代谢的代谢转变,为治疗耐药肺癌的治疗策略提供了新的见解。
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来源期刊
CiteScore
4.00
自引率
2.80%
发文量
577
审稿时长
2 months
期刊介绍: The "Journal of Cancer Research and Clinical Oncology" publishes significant and up-to-date articles within the fields of experimental and clinical oncology. The journal, which is chiefly devoted to Original papers, also includes Reviews as well as Editorials and Guest editorials on current, controversial topics. The section Letters to the editors provides a forum for a rapid exchange of comments and information concerning previously published papers and topics of current interest. Meeting reports provide current information on the latest results presented at important congresses. The following fields are covered: carcinogenesis - etiology, mechanisms; molecular biology; recent developments in tumor therapy; general diagnosis; laboratory diagnosis; diagnostic and experimental pathology; oncologic surgery; and epidemiology.
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