Apatinib attenuates CRKII-Mediated angiogenesis: Possible implications for metastasis prevention from small extracellular vesicle proteomics

IF 6.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology Pub Date : 2026-12-01 Epub Date: 2026-10-20 DOI:10.1016/j.bcp.2026.118555

Shiqin Wei, Yuan Mei, Chunjiang Liu, Weiwei Huang, Suhong Yu

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引用次数: 0

Abstract

High postoperative recurrence severely compromises treatment for triple-negative breast cancer (TNBC) surgical outcomes. We investigated Apatinib’s potential as an adjuvant therapy targeting sEV (Small Extracellular Vesicle)-mediated angiogenesis within the tumor microenvironment to identify novel prognostic biomarkers. We employed quantitative label-free proteomics to screen for key therapeutic targets in TNBC-derived sEVs. The anti-angiogenic efficacy and potential anti-metastatic activity of Apatinib was evaluated using in vitro functional assays (proliferation, migration, adhesion, invasion, and tube formation) and an in vivo TNBC syngeneic mouse model. To validate its translational potential, we analyzed the regulation of the CRKII-PXN/VEGFA axis and its correlation with tumor angiogenesis and growth inhibition. Proteomic analysis identified the adaptor protein CRKII as a central hub significantly downregulated by Apatinib in sEVs. Mechanistically, Apatinib disrupted the transmission of pro-angiogenic signals to endothelial cells by reducing sEV-CRKII (small extracelluar vesicle-CRKII), which subsequently inhibited the downstream CRKII-PXN/VEGFA signaling axis. Functional validation confirmed that CRKII knockdown mimicked, while overexpression reversed, the anti-angiogenic effects of Apatinib. In the preclinical model, Apatinib significantly suppressed tumor growth and reduced microvessel density, suggesting its efficacy in controlling tumor burden and potential micrometastases. Apatinib effectively inhibits TNBC angiogenesis and exhibits potential anti-metastatic activity by downregulating sEV-CRKII and blocking the CRKII-PXN/VEGFA axis. These findings suggest that Apatinib may have potential as a postoperative adjuvant therapy for metastasis prevention. Furthermore, sEV-CRKII emerges as a promising non-invasive biomarker for surgeons to monitor therapeutic response and recurrence risk in TNBC patients.

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阿帕替尼减弱crkii介导的血管生成：可能影响细胞外小泡蛋白组学预防转移。

术后高复发率严重影响了三阴性乳腺癌（TNBC）手术治疗的效果。我们研究了Apatinib作为肿瘤微环境中靶向sEV（小细胞外囊泡）介导的血管生成的辅助治疗的潜力，以确定新的预后生物标志物。我们使用定量无标记蛋白质组学来筛选tnbc衍生sev的关键治疗靶点。通过体外功能测定（增殖、迁移、粘附、侵袭和管形成）和体内TNBC同基因小鼠模型，评估了阿帕替尼的抗血管生成功效和潜在的抗转移活性。为了验证其翻译潜力，我们分析了CRKII-PXN/VEGFA轴的调控及其与肿瘤血管生成和生长抑制的相关性。蛋白质组学分析发现，在sev中，适配器蛋白CRKII是一个被阿帕替尼显著下调的中心枢纽。机制上，Apatinib通过降低sEV-CRKII（小细胞外囊泡- crkii）破坏促血管生成信号向内皮细胞的传递，从而抑制下游的CRKII-PXN/VEGFA信号轴。功能验证证实，CRKII敲低模拟了阿帕替尼的抗血管生成作用，而过表达逆转了这种作用。在临床前模型中，阿帕替尼显著抑制肿瘤生长，降低微血管密度，提示其在控制肿瘤负荷和潜在微转移方面的有效性。Apatinib通过下调sEV-CRKII和阻断CRKII-PXN/VEGFA轴，有效抑制TNBC血管生成，并表现出潜在的抗转移活性。这些发现表明，阿帕替尼可能有潜力作为预防转移的术后辅助治疗。此外，sEV-CRKII成为外科医生监测TNBC患者治疗反应和复发风险的一种有前景的非侵入性生物标志物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biochemical pharmacology 医学-药学

CiteScore

10.30

自引率

1.70%

发文量

420

审稿时长

17 days

期刊介绍： Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics. The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process. All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review. While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.