Inhibition of IL-8/CXCR2 signaling axis prevents tumor growth and metastasis in triple negative breast cancer cells.

IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY
Pharmacology Pub Date : 2025-04-04 DOI:10.1159/000545659
Yisun Jeong, Sun Young Yoon, Seung Pil Jung, Seok Jin Nam, Jeong Eon Lee, Sangmin Kim
{"title":"Inhibition of IL-8/CXCR2 signaling axis prevents tumor growth and metastasis in triple negative breast cancer cells.","authors":"Yisun Jeong, Sun Young Yoon, Seung Pil Jung, Seok Jin Nam, Jeong Eon Lee, Sangmin Kim","doi":"10.1159/000545659","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>Previously, we reported that interleukin-8 (IL-8) was associated with poor prognosis of basal like breast cancer patients and has been identified as a pro-tumorigenic factor, facilitating cell invasion and migration. Here, we investigated the pharmacological impact of inhibitors targeting the chemokine receptors, CXCR1 and CXCR2, which are activated by IL-8.</p><p><strong>Methods: </strong>The survival rates of TNBC patients by IL-8 were analyzed by the Kaplan-Meier plotter. The levels of mRNA and protein expression were analyzed by real-time PCR and western blotting. The alteration of apoptotic cell death-related proteins by SB225002 was analyzed by the Proteome Profiler Human Apoptosis Array. Cell growth was analyzed by MTT and colony forming assay. Apoptosis and cell cycle were analyzed by FACS.</p><p><strong>Results: </strong>Aberrant IL-8 expression is involved with the prognosis of triple-negative breast cancer (TNBC) patients. Basal IL-8 levels are markedly elevated in TNBC cells compared to those in HER2+ and/or ER+ breast cancer cells. Furthermore, recombinant human IL-8 treatment enhanced cell invasiveness in TNBC cells. To counteract the tumor-promoting effects of IL-8, we assessed the therapeutic potential of CXCR1 and CXCR2 inhibitors. Notably, while reparixin, a CXCR1-specific inhibitor, exhibited no impact on cell viability, SB225002, a CXCR2-specific inhibitor, significantly reduced cell viability in a dose-dependent manner. There was a noticeable reduction in the levels of anti-apoptotic biomarkers, including Bcl-2, cIAP-1, cIAP-2, Survivin, XIAP, HIF-1α, and HO-1, following SB225002 treatment. Our findings indicate an increase in the apoptotic cell population with SB225002 treatment in TNBC cells. In xenograft models, SB225002 effectively diminished the metastatic potential of 4T1 cells, which are known to metastasize to the lung and liver.</p><p><strong>Conclusion: </strong>Our results underscore the significant role of the IL-8/CXCR2 signaling axis in the metastasis of TNBC and suggest that CXCR2 inhibitors such as SB225002 may be promising therapeutic agents for TNBC patients.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"1-17"},"PeriodicalIF":2.9000,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1159/000545659","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0

Abstract

Introduction: Previously, we reported that interleukin-8 (IL-8) was associated with poor prognosis of basal like breast cancer patients and has been identified as a pro-tumorigenic factor, facilitating cell invasion and migration. Here, we investigated the pharmacological impact of inhibitors targeting the chemokine receptors, CXCR1 and CXCR2, which are activated by IL-8.

Methods: The survival rates of TNBC patients by IL-8 were analyzed by the Kaplan-Meier plotter. The levels of mRNA and protein expression were analyzed by real-time PCR and western blotting. The alteration of apoptotic cell death-related proteins by SB225002 was analyzed by the Proteome Profiler Human Apoptosis Array. Cell growth was analyzed by MTT and colony forming assay. Apoptosis and cell cycle were analyzed by FACS.

Results: Aberrant IL-8 expression is involved with the prognosis of triple-negative breast cancer (TNBC) patients. Basal IL-8 levels are markedly elevated in TNBC cells compared to those in HER2+ and/or ER+ breast cancer cells. Furthermore, recombinant human IL-8 treatment enhanced cell invasiveness in TNBC cells. To counteract the tumor-promoting effects of IL-8, we assessed the therapeutic potential of CXCR1 and CXCR2 inhibitors. Notably, while reparixin, a CXCR1-specific inhibitor, exhibited no impact on cell viability, SB225002, a CXCR2-specific inhibitor, significantly reduced cell viability in a dose-dependent manner. There was a noticeable reduction in the levels of anti-apoptotic biomarkers, including Bcl-2, cIAP-1, cIAP-2, Survivin, XIAP, HIF-1α, and HO-1, following SB225002 treatment. Our findings indicate an increase in the apoptotic cell population with SB225002 treatment in TNBC cells. In xenograft models, SB225002 effectively diminished the metastatic potential of 4T1 cells, which are known to metastasize to the lung and liver.

Conclusion: Our results underscore the significant role of the IL-8/CXCR2 signaling axis in the metastasis of TNBC and suggest that CXCR2 inhibitors such as SB225002 may be promising therapeutic agents for TNBC patients.

抑制IL-8/CXCR2信号轴抑制三阴性乳腺癌细胞的肿瘤生长和转移。
之前,我们报道了白细胞介素-8 (IL-8)与基底样乳腺癌患者预后不良相关,并已被确定为促瘤因子,促进细胞侵袭和迁移。在这里,我们研究了靶向趋化因子受体CXCR1和CXCR2的抑制剂的药理学影响,这些受体被IL-8激活。方法:应用Kaplan-Meier绘图仪分析TNBC患者IL-8的生存率。实时荧光定量PCR和western blotting分析mRNA和蛋白表达水平。用Proteome Profiler Human Apoptosis Array分析SB225002对凋亡细胞死亡相关蛋白的改变。用MTT法和菌落形成法分析细胞生长情况。流式细胞仪分析细胞凋亡和细胞周期。结果:IL-8的异常表达与三阴性乳腺癌(TNBC)患者的预后有关。与HER2+和/或ER+乳腺癌细胞相比,TNBC细胞的基础IL-8水平明显升高。此外,重组人IL-8处理增强了TNBC细胞的侵袭性。为了抵消IL-8的促肿瘤作用,我们评估了CXCR1和CXCR2抑制剂的治疗潜力。值得注意的是,虽然cxcr1特异性抑制剂reparixin对细胞活力没有影响,但cxcr2特异性抑制剂SB225002却以剂量依赖性的方式显著降低细胞活力。SB225002治疗后,抗凋亡生物标志物(包括Bcl-2、cIAP-1、cIAP-2、Survivin、XIAP、HIF-1α和HO-1)水平明显降低。我们的研究结果表明,SB225002治疗TNBC细胞的凋亡细胞数量增加。在异种移植模型中,SB225002有效地降低了4T1细胞的转移潜力,已知4T1细胞转移到肺和肝脏。结论:我们的研究结果强调了IL-8/CXCR2信号轴在TNBC转移中的重要作用,并提示CXCR2抑制剂如SB225002可能是TNBC患者有希望的治疗药物。
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
Pharmacology
Pharmacology 医学-药学
CiteScore
5.60
自引率
0.00%
发文量
52
审稿时长
6-12 weeks
期刊介绍: ''Pharmacology'' is an international forum to present and discuss current perspectives in drug research. The journal communicates research in basic and clinical pharmacology and related fields. It covers biochemical pharmacology, molecular pharmacology, immunopharmacology, drug metabolism, pharmacogenetics, analytical toxicology, neuropsychopharmacology, pharmacokinetics and clinical pharmacology. In addition to original papers and short communications of investigative findings and pharmacological profiles the journal contains reviews, comments and perspective notes; research communications of novel therapeutic agents are encouraged.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信