Anlotinib增强膀胱癌GSDMB表达的治疗效果——来自TCGA膀胱癌数据库和小鼠膀胱癌细胞株的分析

IF 1.8 4区 医学 Q3 PHARMACOLOGY & PHARMACY Pharmacogenomics & Personalized Medicine Pub Date : 2023-01-01 DOI:10.2147/PGPM.S398451
Chen Wang, Qifeng Cao, Shun Zhang, Hailong Liu, Huangqi Duan, Weimin Xia, Haibo Shen, Cheng Wang
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引用次数: 0

摘要

简介与目的:丝裂原活化蛋白激酶(MAPK)通路被泛靶点抑制剂Anlotinib抑制,诱导肿瘤细胞死亡。除了常见的凋亡和坏死外,近年来还出现了一种肿瘤细胞死亡的焦亡模式,主要表现为gasdermin蛋白(GSDMs)的裂解。Gasdermin B (GSDMB)参与膀胱癌的进展和预后。Anlotinib治疗gsdmb阳性膀胱肿瘤的疗效及作用机制至今未见研究。方法:从TCGA膀胱癌数据库中分析GSDMB表达与肿瘤分期、总生存率、免疫治疗应答、肿瘤复发及进展率的关系。应用Anlotinib治疗小鼠gsdmb阳性膀胱癌,然后流式分析与焦亡相关的炎性因子分泌及抗肿瘤因子水平。Western blot分析检测了MAPK和MEK信号转导通路。结果:TCGA数据分析显示,GSDMB高表达膀胱癌患者的总生存率优于GSDMB低表达膀胱癌患者。体内实验表明,Anlotinib治疗gsdmb阳性膀胱癌比gsdmb阴性膀胱癌更有效。Anlotinib可增加gsdmb阳性膀胱癌中TNF-a、CD107a等抗肿瘤相关因子的分泌。此外,Anlotinib还诱导GSDMB蛋白表达增加。安洛替尼治疗gsdmb阳性膀胱癌可降低参与安洛替尼信号转导通路的AKT和MEK蛋白的表达。结论:安洛替尼对gsdmb阳性膀胱肿瘤具有较强的抗肿瘤作用。这种作用主要是通过anlotinib刺激淋巴细胞分泌相关抗肿瘤因子来实现的。在表达GSDMB蛋白的膀胱癌中,Anlotinib可抑制PI3K/AKT和MEK信号转导通路。
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Anlotinib Enhances the Therapeutic Effect of Bladder Cancer with GSDMB Expression: Analyzed from TCGA Bladder Cancer Database & Mouse Bladder Cancer Cell Line.

Introduction and objective: The mitogen-activated protein kinase (MAPK) pathway is inhibited by the pan-target inhibitor Anlotinib, which induces tumor cell death. In addition to the common apoptosis and necrosis, there is also a pyroptosis mode of cancer cell death in recent years, which is mainly manifested by the cleavage of gasdermin proteins (GSDMs). Gasdermin B (GSDMB) participates in the progression and outcome of bladder cancer. The efficacy and mechanism of Anlotinib in the treatment of GSDMB-positive bladder tumors have not been studied to date.

Methods: The relationship between GSDMB expression and tumor stage, overall survival rate, immunotherapy response, tumor recurrence and progression rate was analyzed from the TCGA bladder cancer database. Anlotinib was used to treat GSDMB-positive bladder cancer in mice followed by flow analysis of the secretion of inflammatory factors related to pyroptosis and the level of anti-tumor factors. Western blot analysis detected which MAPK and MEK signal transduction pathways.

Results: TCGA data analysis showed that the overall survival rate of bladder cancer patients with high GSDMB expression was better than that of patients with low GSDMB expression. In vivo experiments showed that Anlotinib was more effective in the treatment of GSDMB-positive bladder cancer than GSDMB-negative bladder cancer. Anlotinib can increase the secretion of antitumor-related factors in GSDMB-positive bladder cancer such as TNF-a and CD107a. In addition, Anlotinib also induced an increase in GSDMB protein expression. Anlotinib treatment of GSDMB-positive bladder cancer decreased AKT and MEK protein expression, which were involved in Anlotinib signal transduction pathway.

Conclusion: Anlotinib has a strong antitumor effect on GSDMB-positive bladder tumors. This effect is mainly achieved by anlotinib stimulating the secretion of relevant antitumor factors by lymphocytes. The PI3K/AKT and MEK signal transduction pathways were inhibited by Anlotinib in bladder cancer expressing GSDMB protein.

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来源期刊
Pharmacogenomics & Personalized Medicine
Pharmacogenomics & Personalized Medicine Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
3.30
自引率
5.30%
发文量
110
审稿时长
16 weeks
期刊介绍: Pharmacogenomics and Personalized Medicine is an international, peer-reviewed, open-access journal characterizing the influence of genotype on pharmacology leading to the development of personalized treatment programs and individualized drug selection for improved safety, efficacy and sustainability. In particular, emphasis will be given to: Genomic and proteomic profiling Genetics and drug metabolism Targeted drug identification and discovery Optimizing drug selection & dosage based on patient''s genetic profile Drug related morbidity & mortality intervention Advanced disease screening and targeted therapeutic intervention Genetic based vaccine development Patient satisfaction and preference Health economic evaluations Practical and organizational issues in the development and implementation of personalized medicine programs.
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