宝藿苷 I 通过抑制凋亡细胞释放的细胞外囊泡/CXCL1 信号,使乳腺癌对紫杉醇产生化疗敏感性。

IF 15.5 1区 医学 Q1 CELL BIOLOGY Journal of Extracellular Vesicles Pub Date : 2024-07-25 DOI:10.1002/jev2.12493
Shengqi Wang, Jing Li, Shang Xu, Neng Wang, Bo Pan, Bowen Yang, Yifeng Zheng, Juping Zhang, Fu Peng, Cheng Peng, Zhiyu Wang
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引用次数: 0

摘要

三阴性乳腺癌(TNBC)是侵袭性最强的乳腺癌亚型,化疗是治疗 TNBC 的基础疗法。令人遗憾的是,新的研究结果表明,化疗促进了肿瘤微环境的转移变化。细胞外囊泡(EVs)与癌症的耐药性和转移密切相关。然而,从濒死癌细胞中释放的EVs对TNBC预后的影响以及相应的治疗策略还鲜有研究。本研究表明,紫杉醇化疗可诱导凋亡的TNBC细胞产生富含CXCL1的EVs(EV-Apo)。EV-Apo通过激活PD-L1信号,使M2巨噬细胞极化,从而促进了共培养TNBC细胞的化疗耐药性和侵袭。然而,宝藿苷I(BHS)通过调节EV-Apo信号传导,显著提高了共培养TNBC细胞对紫杉醇化疗的敏感性。从机理上讲,BHS 显著减少了 EV-Apo 中的 C-X-C motif 趋化因子配体 1(CXCL1)载体,从而通过抑制 PD-L1 的活化减轻了巨噬细胞的 M2 极化。此外,BHS还通过减少TNBC细胞多泡体(MVB)内腔内囊泡(ILV)的生物生成来减少EV-Apo的释放。此外,BHS还能与flotillin 2(FLOT2)的LEU104残基结合,中断其与RAS癌基因家族成员31(RAB31)的相互作用,从而阻断RAB31-FLOT2复合物驱动的ILV生物生成。重要的是,BHS通过抑制EV-ApoCXCL1诱导的PD-L1活化和肿瘤相关巨噬细胞(TAMs)的M2极化,显著提高了紫杉醇的化疗敏感性,从而抑制了TNBC在体内的转移。这项开创性的研究揭示了EV-ApoCXCL1作为一种新型治疗靶点对TNBC化疗的敏感性,并将BHS作为一种有前景的化疗辅助剂,通过干扰EV-ApoCXCL1的生物生成来改善TNBC的化疗敏感性和预后。
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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Baohuoside I chemosensitises breast cancer to paclitaxel by suppressing extracellular vesicle/CXCL1 signal released from apoptotic cells

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and chemotherapy is the cornerstone treatment for TNBC. Regrettably, emerging findings suggest that chemotherapy facilitates pro-metastatic changes in the tumour microenvironment. Extracellular vesicles (EVs) have been highly implicated in cancer drug resistance and metastasis. However, the effects of the EVs released from dying cancer cells on TNBC prognosis and corresponding therapeutic strategies have been poorly investigated. This study demonstrated that paclitaxel chemotherapy elicited CXCL1-enriched EVs from apoptotic TNBC cells (EV-Apo). EV-Apo promoted the chemoresistance and invasion of co-cultured TNBC cells by polarizing M2 macrophages through activating PD-L1 signalling. However, baohuoside I (BHS) remarkably sensitized the co-cultured TNBC cells to paclitaxel chemotherapy via modulating EV-Apo signalling. Mechanistically, BHS remarkably decreased C-X-C motif chemokine ligand 1 (CXCL1) cargo within EV-Apo and therefore attenuated macrophage M2 polarization by suppressing PD-L1 activation. Additionally, BHS decreased EV-Apo release by diminishing the biogenesis of intraluminal vesicles (ILVs) within multivesicular bodies (MVBs) of TNBC cells. Furthermore, BHS bound to the LEU104 residue of flotillin 2 (FLOT2) and interrupted its interaction with RAS oncogene family member 31 (RAB31), leading to the blockage of RAB31-FLOT2 complex-driven ILV biogenesis. Importantly, BHS remarkably chemosensitised paclitaxel to inhibit TNBC metastasis in vivo by suppressing EV-ApoCXCL1-induced PD-L1 activation and M2 polarization of tumour-associated macrophages (TAMs). This pioneering study sheds light on EV-ApoCXCL1 as a novel therapeutic target to chemosensitise TNBC, and presents BHS as a promising chemotherapy adjuvant to improve TNBC chemosensitivity and prognosis by disturbing EV-ApoCXCL1 biogenesis.

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来源期刊
Journal of Extracellular Vesicles
Journal of Extracellular Vesicles Biochemistry, Genetics and Molecular Biology-Cell Biology
CiteScore
27.30
自引率
4.40%
发文量
115
审稿时长
12 weeks
期刊介绍: The Journal of Extracellular Vesicles is an open access research publication that focuses on extracellular vesicles, including microvesicles, exosomes, ectosomes, and apoptotic bodies. It serves as the official journal of the International Society for Extracellular Vesicles and aims to facilitate the exchange of data, ideas, and information pertaining to the chemistry, biology, and applications of extracellular vesicles. The journal covers various aspects such as the cellular and molecular mechanisms of extracellular vesicles biogenesis, technological advancements in their isolation, quantification, and characterization, the role and function of extracellular vesicles in biology, stem cell-derived extracellular vesicles and their biology, as well as the application of extracellular vesicles for pharmacological, immunological, or genetic therapies. The Journal of Extracellular Vesicles is widely recognized and indexed by numerous services, including Biological Abstracts, BIOSIS Previews, Chemical Abstracts Service (CAS), Current Contents/Life Sciences, Directory of Open Access Journals (DOAJ), Journal Citation Reports/Science Edition, Google Scholar, ProQuest Natural Science Collection, ProQuest SciTech Collection, SciTech Premium Collection, PubMed Central/PubMed, Science Citation Index Expanded, ScienceOpen, and Scopus.
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