Cancer-Associated Fibroblast-Derived RIPK4 Confers Cisplatin Resistance in Gastric Cancer by Activating the PI3K/AKT Pathway

IF 3.2 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Biochemical and Molecular Toxicology Pub Date : 2025-06-16 DOI:10.1002/jbt.70320

Rui Chen, Junfang Dai, Bo Wang, Guofei Peng, Yao Xun, Yan Li

{"title":"Cancer-Associated Fibroblast-Derived RIPK4 Confers Cisplatin Resistance in Gastric Cancer by Activating the PI3K/AKT Pathway","authors":"Rui Chen, Junfang Dai, Bo Wang, Guofei Peng, Yao Xun, Yan Li","doi":"10.1002/jbt.70320","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n <p>Cancer-associated fibroblasts (CAFs) play a central role in cancer progression and are involved in modulating cancer cell proliferation, invasion, metastasis, drug resistance and so on. Receptor Interacting Serine/Threonine Kinase 4 (RIPK4) was demonstrated to promote gastric cancer (GC) metastasis and tumorigenesis. Here, this study aimed to explore whether GC-derived CAFs affected cisplatin (DDP) resistance in GC cells via RIPK4. DDP-resistant GC cells were first established. Levels of RIPK4 mRNA and proteins were detected using qRT-PCR and western blotting. The IC50 values of DDP, cell proliferation, invasion, and migration were analyzed using MTT, 5-ethynyl-2′-deoxyuridine, transwell, and wound healing assays, respectively. PI3K/AKT pathway-related proteins were measured by western blotting. Animal experiments were performed for in vivo analysis. Here, we found that CAFs enhanced DDP resistance in DDP-resistant cells by promoting cell proliferation, invasion and migration. CAFs led to an increased RIPK4 expression in DDP-resistant cells. The silencing of RIPK4 suppressed DDP resistance in DDP-resistant cells. Moreover, RIPK4 silencing in CAFs could also reduce DDP resistance in GC. Mechanistically, CAFs could activate the PI3K/AKT pathway by RIPK4. In vivo assay also showed that RIPK4 silencing in CAFs attenuated CAF-induced DDP resistance. In conclusion, RIPK4-decreased CAFs suppressed DDP resistance in GC by blocking the activation of the PI3K/AKT pathway, recommending a novel method for overcoming DDP resistance in gastric cancer.</p>\n </section>\n </div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 6","pages":""},"PeriodicalIF":3.2000,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Biochemical and Molecular Toxicology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/jbt.70320","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Cancer-associated fibroblasts (CAFs) play a central role in cancer progression and are involved in modulating cancer cell proliferation, invasion, metastasis, drug resistance and so on. Receptor Interacting Serine/Threonine Kinase 4 (RIPK4) was demonstrated to promote gastric cancer (GC) metastasis and tumorigenesis. Here, this study aimed to explore whether GC-derived CAFs affected cisplatin (DDP) resistance in GC cells via RIPK4. DDP-resistant GC cells were first established. Levels of RIPK4 mRNA and proteins were detected using qRT-PCR and western blotting. The IC50 values of DDP, cell proliferation, invasion, and migration were analyzed using MTT, 5-ethynyl-2′-deoxyuridine, transwell, and wound healing assays, respectively. PI3K/AKT pathway-related proteins were measured by western blotting. Animal experiments were performed for in vivo analysis. Here, we found that CAFs enhanced DDP resistance in DDP-resistant cells by promoting cell proliferation, invasion and migration. CAFs led to an increased RIPK4 expression in DDP-resistant cells. The silencing of RIPK4 suppressed DDP resistance in DDP-resistant cells. Moreover, RIPK4 silencing in CAFs could also reduce DDP resistance in GC. Mechanistically, CAFs could activate the PI3K/AKT pathway by RIPK4. In vivo assay also showed that RIPK4 silencing in CAFs attenuated CAF-induced DDP resistance. In conclusion, RIPK4-decreased CAFs suppressed DDP resistance in GC by blocking the activation of the PI3K/AKT pathway, recommending a novel method for overcoming DDP resistance in gastric cancer.

Abstract Image

查看原文本刊更多论文

癌症相关成纤维细胞衍生的RIPK4通过激活PI3K/AKT通路赋予胃癌顺铂耐药

癌症相关成纤维细胞（cancer -associated fibroblasts, CAFs）在癌症的发展过程中起着核心作用，参与调节癌细胞的增殖、侵袭、转移、耐药等过程。受体相互作用丝氨酸/苏氨酸激酶4 （RIPK4）被证实促进胃癌（GC）的转移和肿瘤发生。本研究旨在探讨GC源性CAFs是否通过RIPK4影响GC细胞对顺铂（DDP）的耐药。首先建立耐ddp的GC细胞。采用qRT-PCR和western blotting检测RIPK4 mRNA和蛋白水平。分别采用MTT、5-乙基-2′-脱氧尿苷、transwell和伤口愈合试验分析DDP、细胞增殖、侵袭和迁移的IC50值。western blotting检测PI3K/AKT通路相关蛋白。采用动物实验进行体内分析。在这里，我们发现CAFs通过促进DDP抗性细胞的增殖、侵袭和迁移来增强DDP抗性细胞。CAFs导致ddp耐药细胞中RIPK4表达增加。RIPK4的沉默抑制了DDP耐药细胞对DDP的抗性。此外，CAFs中RIPK4的沉默也可以降低GC对DDP的抗性。在机制上，CAFs可以通过RIPK4激活PI3K/AKT通路。体内实验还显示，在CAFs中，RIPK4沉默可减弱CAFs诱导的DDP抗性。综上所述，ripk4减少的CAFs通过阻断PI3K/AKT通路的激活来抑制胃癌DDP耐药，为克服胃癌DDP耐药提供了一种新的方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Journal of Biochemical and Molecular Toxicology 生物-毒理学

CiteScore

5.80

自引率

2.80%

发文量

277

审稿时长

6-12 weeks

期刊介绍： The Journal of Biochemical and Molecular Toxicology is an international journal that contains original research papers, rapid communications, mini-reviews, and book reviews, all focusing on the molecular mechanisms of action and detoxication of exogenous and endogenous chemicals and toxic agents. The scope includes effects on the organism at all stages of development, on organ systems, tissues, and cells as well as on enzymes, receptors, hormones, and genes. The biochemical and molecular aspects of uptake, transport, storage, excretion, lactivation and detoxication of drugs, agricultural, industrial and environmental chemicals, natural products and food additives are all subjects suitable for publication. Of particular interest are aspects of molecular biology related to biochemical toxicology. These include studies of the expression of genes related to detoxication and activation enzymes, toxicants with modes of action involving effects on nucleic acids, gene expression and protein synthesis, and the toxicity of products derived from biotechnology.