Mechanistic insights of lenvatinib: enhancing cisplatin sensitivity, inducing apoptosis, and suppressing metastasis in bladder cancer cells through EGFR/ERK/P38/NF-κB signaling inactivation.

IF 5.3 2区医学 Q1 ONCOLOGY

Cancer Cell International Pub Date : 2025-02-15 DOI:10.1186/s12935-024-03597-7

Chih-Hung Chiang, Jr-Di Yang, Wei-Lin Liu, Fang-Yu Chang, Che-Jui Yang, Kai-Wen Hsu, I-Tsang Chiang, Fei-Ting Hsu

{"title":"Mechanistic insights of lenvatinib: enhancing cisplatin sensitivity, inducing apoptosis, and suppressing metastasis in bladder cancer cells through EGFR/ERK/P38/NF-κB signaling inactivation.","authors":"Chih-Hung Chiang, Jr-Di Yang, Wei-Lin Liu, Fang-Yu Chang, Che-Jui Yang, Kai-Wen Hsu, I-Tsang Chiang, Fei-Ting Hsu","doi":"10.1186/s12935-024-03597-7","DOIUrl":null,"url":null,"abstract":"Background: The persistent activation of the epidermal growth factor receptor (EGFR) leads to the activation of downstream oncogenic kinases and transcription factors, resulting in tumor progression and an increased resistance to cisplatin in bladder cancer (BC) cells. Lenvatinib, an oral multikinase inhibitor, has the potential to offer therapeutic benefits as an adjuvant treatment for BC patients. The investigation into its application in bladder cancer treatment is a valuable endeavor. The primary goal of this study is to confirm the effectiveness and mechanism of lenvatinib in inhibiting the progression of BC and enhancing the anticancer efficacy of cisplatin.Materials: Three BC cell lines, namely, TSGH-8301, T24, and MB49, along with an MB49-bearing animal model, were utilized in this study.Results: In vitro experiments utilizing MTT assays demonstrated that lenvatinib sensitized BC cells to cisplatin, exhibiting a synergistic effect. Flow cytometry indicated apoptotic events and signaling, presenting that lenvatinib effectively induced apoptosis and triggered extrinsic/intrinsic apoptotic pathways. In vivo studies using a mouse model of BC confirmed the antitumor efficacy of lenvatinib, demonstrating significant tumor growth suppression without inducing toxicity in normal tissues. Western blotting analysis and immunohistochemistry stain revealed EGF-phosphorylated EGFR and EGFR-mediated ERK/P38/NF-κB signaling were suppressed by treatment with lenvatinib. In addition, lenvatinib also suppressed anti-apoptotic (MCL1, c-FLIP, and XIAP) and metastasis-related factors (Twist, Snail-1, ZEB-1, ZEB-2, and MMP9) and promoted epithelial markers (E-cadherin) while reducing mesenchymal markers (N-cadherin).Conclusion: In conclusion, the induction of apoptosis and the inhibition of EGFR/ERK/P38/NF-κB signaling are correlated with lenvatinib's ability to hinder tumor progression and enhance the cytotoxic effects of cisplatin in bladder cancer. These findings underscore the potential of lenvatinib as a therapeutic option for bladder cancer, either as a standalone treatment or in combination with cisplatin.","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"47"},"PeriodicalIF":5.3000,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11829490/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Cell International","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s12935-024-03597-7","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Background: The persistent activation of the epidermal growth factor receptor (EGFR) leads to the activation of downstream oncogenic kinases and transcription factors, resulting in tumor progression and an increased resistance to cisplatin in bladder cancer (BC) cells. Lenvatinib, an oral multikinase inhibitor, has the potential to offer therapeutic benefits as an adjuvant treatment for BC patients. The investigation into its application in bladder cancer treatment is a valuable endeavor. The primary goal of this study is to confirm the effectiveness and mechanism of lenvatinib in inhibiting the progression of BC and enhancing the anticancer efficacy of cisplatin.

Materials: Three BC cell lines, namely, TSGH-8301, T24, and MB49, along with an MB49-bearing animal model, were utilized in this study.

Results: In vitro experiments utilizing MTT assays demonstrated that lenvatinib sensitized BC cells to cisplatin, exhibiting a synergistic effect. Flow cytometry indicated apoptotic events and signaling, presenting that lenvatinib effectively induced apoptosis and triggered extrinsic/intrinsic apoptotic pathways. In vivo studies using a mouse model of BC confirmed the antitumor efficacy of lenvatinib, demonstrating significant tumor growth suppression without inducing toxicity in normal tissues. Western blotting analysis and immunohistochemistry stain revealed EGF-phosphorylated EGFR and EGFR-mediated ERK/P38/NF-κB signaling were suppressed by treatment with lenvatinib. In addition, lenvatinib also suppressed anti-apoptotic (MCL1, c-FLIP, and XIAP) and metastasis-related factors (Twist, Snail-1, ZEB-1, ZEB-2, and MMP9) and promoted epithelial markers (E-cadherin) while reducing mesenchymal markers (N-cadherin).

Conclusion: In conclusion, the induction of apoptosis and the inhibition of EGFR/ERK/P38/NF-κB signaling are correlated with lenvatinib's ability to hinder tumor progression and enhance the cytotoxic effects of cisplatin in bladder cancer. These findings underscore the potential of lenvatinib as a therapeutic option for bladder cancer, either as a standalone treatment or in combination with cisplatin.

查看原文本刊更多论文

lenvatinib的作用机制：通过EGFR/ERK/P38/NF-κB信号失活，增强顺铂敏感性，诱导细胞凋亡，抑制膀胱癌细胞转移。

背景：表皮生长因子受体（EGFR）的持续激活导致下游致癌激酶和转录因子的激活，导致膀胱癌（BC）细胞的肿瘤进展和对顺铂的耐药性增加。Lenvatinib是一种口服多激酶抑制剂，有可能作为BC患者的辅助治疗提供治疗益处。探讨其在膀胱癌治疗中的应用是一项有价值的尝试。本研究的主要目的是确认lenvatinib抑制BC进展、增强顺铂抗癌疗效的有效性和机制。材料：采用3株BC细胞系TSGH-8301、T24和MB49，并建立了携带MB49的动物模型。结果：体外MTT实验表明，lenvatinib使BC细胞对顺铂增敏，表现出协同效应。流式细胞术显示凋亡事件和信号，表明lenvatinib有效诱导细胞凋亡并触发外源性/内源性凋亡通路。使用小鼠BC模型进行的体内研究证实了lenvatinib的抗肿瘤功效，在正常组织中显示出明显的肿瘤生长抑制作用，而不诱导毒性。Western blotting分析和免疫组化染色显示lenvatinib可抑制egf磷酸化的EGFR和EGFR介导的ERK/P38/NF-κB信号通路。此外，lenvatinib还抑制抗凋亡因子（MCL1、c-FLIP和XIAP）和转移相关因子（Twist、Snail-1、ZEB-1、ZEB-2和MMP9），促进上皮标志物（E-cadherin），降低间质标志物（N-cadherin）。结论：综上所述，lenvatinib诱导膀胱癌细胞凋亡、抑制EGFR/ERK/P38/NF-κB信号通路与lenvatinib抑制肿瘤进展、增强顺铂对膀胱癌细胞毒作用相关。这些发现强调了lenvatinib作为膀胱癌治疗选择的潜力，无论是单独治疗还是与顺铂联合治疗。

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

Cancer Cell International ONCOLOGY-

CiteScore

10.90

自引率

1.70%

发文量

360

审稿时长

1 months

期刊介绍： Cancer Cell International publishes articles on all aspects of cancer cell biology, originating largely from, but not limited to, work using cell culture techniques. The journal focuses on novel cancer studies reporting data from biological experiments performed on cells grown in vitro, in two- or three-dimensional systems, and/or in vivo (animal experiments). These types of experiments have provided crucial data in many fields, from cell proliferation and transformation, to epithelial-mesenchymal interaction, to apoptosis, and host immune response to tumors. Cancer Cell International also considers articles that focus on novel technologies or novel pathways in molecular analysis and on epidemiological studies that may affect patient care, as well as articles reporting translational cancer research studies where in vitro discoveries are bridged to the clinic. As such, the journal is interested in laboratory and animal studies reporting on novel biomarkers of tumor progression and response to therapy and on their applicability to human cancers.