BCAR1 facilitates the survival of lung adenocarcinoma cells by augmenting the unfolded protein response, autophagy, and the formation of vasculogenic mimicry

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease Pub Date : 2024-10-31 DOI:10.1016/j.bbadis.2024.167558

Chengyi Mao , Jingge Zhang , Chuan Yang , Longyong Mei , Yonggeng Feng , Fuqiang Dai , Yi Huang , Hualiang Xiao , Bo Deng

{"title":"BCAR1 facilitates the survival of lung adenocarcinoma cells by augmenting the unfolded protein response, autophagy, and the formation of vasculogenic mimicry","authors":"Chengyi Mao , Jingge Zhang , Chuan Yang , Longyong Mei , Yonggeng Feng , Fuqiang Dai , Yi Huang , Hualiang Xiao , Bo Deng","doi":"10.1016/j.bbadis.2024.167558","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>Our objective was to elucidate the pivotal roles of BCAR1 in unfolded protein response (UPR), autophagy and vasculogenic mimicry (VM) formation, processes that essential for the metastasis of lung adenocarcinoma (LUAD) cells.</div></div><div><h3>Methods</h3><div>The morphological assessment of endoplasmic reticulum (ER) status and autolysosomes in H1975 and H1299 LUAD cells following BCAR1 knockout (KO) was conducted using transmission electron microscope. The expression of markers and cellular functions related to the UPR, autophagy, and VM formation were examined in LUAD cells tissues. Additionally, proteomic analysis of LUAD cells was performed via mass spectrometry, and the pertinent signaling pathways were analyzed using bioinformatics tools.</div></div><div><h3>Results</h3><div>BCAR1-KO inhibited autophagy and UPR induced triggered starvation in LUAD cells. Cleaved-ATF6a-mediated UPR and subsequent autophagy, enhanced by BCAR1, were confirmed using the UPR stimulator and blocker. High BCAR1 expression, along with elevated UPR and autophagy, predicts poor prognosis in LUAD patients. BCAR1-KO reduced tube formation and VM markers expressions in LUAD cells. Additionally, BCAR1 expression positively correlated with VM formation in BALB/c-nu mice xenografts and LUAD patient tissues.</div></div><div><h3>Conclusion</h3><div>BCAR1 promotes LUAD metastasis by enhancing cancer cell survival in nutrient-poor environments through ATF6-mediated UPR activation and autophagy. As BCAR1 induces VM formation, metastatic lesions eventually colonize. Thus, BCAR1 is a promising anti-metastasis target.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167558"},"PeriodicalIF":4.2000,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biochimica et biophysica acta. Molecular basis of disease","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0925443924005520","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Background

Our objective was to elucidate the pivotal roles of BCAR1 in unfolded protein response (UPR), autophagy and vasculogenic mimicry (VM) formation, processes that essential for the metastasis of lung adenocarcinoma (LUAD) cells.

Methods

The morphological assessment of endoplasmic reticulum (ER) status and autolysosomes in H1975 and H1299 LUAD cells following BCAR1 knockout (KO) was conducted using transmission electron microscope. The expression of markers and cellular functions related to the UPR, autophagy, and VM formation were examined in LUAD cells tissues. Additionally, proteomic analysis of LUAD cells was performed via mass spectrometry, and the pertinent signaling pathways were analyzed using bioinformatics tools.

Results

BCAR1-KO inhibited autophagy and UPR induced triggered starvation in LUAD cells. Cleaved-ATF6a-mediated UPR and subsequent autophagy, enhanced by BCAR1, were confirmed using the UPR stimulator and blocker. High BCAR1 expression, along with elevated UPR and autophagy, predicts poor prognosis in LUAD patients. BCAR1-KO reduced tube formation and VM markers expressions in LUAD cells. Additionally, BCAR1 expression positively correlated with VM formation in BALB/c-nu mice xenografts and LUAD patient tissues.

Conclusion

BCAR1 promotes LUAD metastasis by enhancing cancer cell survival in nutrient-poor environments through ATF6-mediated UPR activation and autophagy. As BCAR1 induces VM formation, metastatic lesions eventually colonize. Thus, BCAR1 is a promising anti-metastasis target.

查看原文本刊更多论文

BCAR1 通过增强未折叠蛋白反应、自噬和血管生成模拟的形成来促进肺腺癌细胞的存活。

背景：我们的目的是阐明BCAR1在未折叠蛋白反应（UPR）、自噬和血管生成模拟（VM）形成过程中的关键作用，这些过程对肺腺癌（LUAD）细胞的转移至关重要：方法：利用透射电子显微镜对 BCAR1 基因敲除（KO）后的 H1975 和 H1299 LUAD 细胞的内质网（ER）状态和自溶体进行形态学评估。研究还检测了LUAD细胞组织中与UPR、自噬和VM形成相关的标记物表达和细胞功能。此外，还通过质谱对LUAD细胞进行了蛋白质组学分析，并使用生物信息学工具分析了相关信号通路：结果：BCAR1-KO抑制了LUAD细胞的自噬和UPR诱导的饥饿。利用UPR刺激剂和阻断剂证实了BCAR1介导的Cleaved-ATF6a UPR和随后的自噬。BCAR1的高表达以及UPR和自噬的升高可预测LUAD患者的不良预后。BCAR1-KO 可减少 LUAD 细胞中的管形成和 VM 标记表达。此外，BCAR1的表达与BALB/c-nu小鼠异种移植和LUAD患者组织中VM的形成呈正相关：结论：BCAR1通过ATF6介导的UPR激活和自噬，提高了癌细胞在营养不良环境中的存活率，从而促进了LUAD的转移。由于 BCAR1 能诱导 VM 形成，转移病灶最终会定植。因此，BCAR1 是一个很有前景的抗转移靶点。

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

Biochimica et biophysica acta. Molecular basis of disease 生物-生化与分子生物学

CiteScore

12.30

自引率

0.00%

发文量

218

审稿时长

32 days

期刊介绍： BBA Molecular Basis of Disease addresses the biochemistry and molecular genetics of disease processes and models of human disease. This journal covers aspects of aging, cancer, metabolic-, neurological-, and immunological-based disease. Manuscripts focused on using animal models to elucidate biochemical and mechanistic insight in each of these conditions, are particularly encouraged. Manuscripts should emphasize the underlying mechanisms of disease pathways and provide novel contributions to the understanding and/or treatment of these disorders. Highly descriptive and method development submissions may be declined without full review. The submission of uninvited reviews to BBA - Molecular Basis of Disease is strongly discouraged, and any such uninvited review should be accompanied by a coverletter outlining the compelling reasons why the review should be considered.