G-Protein-Coupled Receptor 5 (LGR5) Overexpression Activates β-Catenin Signaling in Breast Cancer Cells via Protein Kinase A.

IF 16.4 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Accounts of Chemical Research Pub Date : 2019-01-21 DOI:10.12659/MSMBR.912411
Zhishui Chen, Chengjun Xue
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引用次数: 8

Abstract

BACKGROUND Targeting cancer stem cells (CSCs) in breast cancer (BrCa) may improve treatment outcome and patient prognosis. Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is a well-recognized adult stem cell and CRC marker, and previous reports have suggested the cancer-promoting role of LGR5 in breast cancer, but the mechanism remains unclear. MATERIAL AND METHODS Potential LGR5-associating genes were explored using STRING database, and LGR5 overexpression and knockdown was constructed in MCF-7 and MDA-MB-453 human BrCa cells, respectively. PKA catalytic subunit activation and PKA kinase activity in human BrCa cells was examined by Western blot and PKA kinase activity assay, respectively. Protein expression level or activation of β-catenin and GSK-3β in human BrCa cells was investigated by Western blot. Cell proliferation, colony formation, Transwell migration, cisplatin sensitivity, and in vivo tumor formation of human BrCa cells were examined. RESULTS LGR5 overexpression increased PKA activation and its kinase activity in human BrCa cells, which was decreased by LGR5 knockdown. LGR5 expression level or PKA kinase activity were correlated with β-catenin Ser 552 phosphorylation but inversely correlated with GSK-3β Ser9 phosphorylation in human BrCa cells in vitro. LGR5/PKA increased cell proliferation, colony formation, Transwell migration, and cisplatin resistance in vitro, as well as tumor formation in vivo, of human BrCa cells. CONCLUSIONS LGR5 activates the Wnt/β-catenin signaling pathway in human BrCa cells in vitro via PKA.

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g蛋白偶联受体5 (LGR5)过表达通过蛋白激酶A激活乳腺癌细胞β-Catenin信号传导
背景:在乳腺癌(BrCa)中靶向肿瘤干细胞(CSCs)可能改善治疗结果和患者预后。Leucine-rich repeat-containing g -protein偶联受体5 (LGR5)是一种公认的成体干细胞和结直肠癌标志物,以前的报道表明LGR5在乳腺癌中具有促癌作用,但其机制尚不清楚。材料与方法利用STRING数据库寻找潜在的LGR5相关基因,分别在MCF-7和MDA-MB-453人BrCa细胞中构建LGR5过表达和低表达基因。Western blot和PKA激酶活性测定分别检测了PKA在人BrCa细胞中的催化亚基活化和PKA激酶活性。Western blot检测β-catenin和GSK-3β在人BrCa细胞中的表达水平或活化情况。研究了人类BrCa细胞的细胞增殖、集落形成、Transwell迁移、顺铂敏感性和体内肿瘤形成。结果LGR5过表达增加了人BrCa细胞中PKA的激活及其激酶活性,而LGR5敲低则降低了PKA的活性。体外培养的人BrCa细胞中,LGR5表达水平或PKA激酶活性与β-catenin Ser 552磷酸化相关,与GSK-3β Ser9磷酸化负相关。LGR5/PKA在体外增加了人类BrCa细胞的细胞增殖、集落形成、Transwell迁移、顺铂耐药性以及体内肿瘤形成。结论LGR5在体外通过PKA激活人BrCa细胞中的Wnt/β-catenin信号通路。
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来源期刊
Accounts of Chemical Research
Accounts of Chemical Research 化学-化学综合
CiteScore
31.40
自引率
1.10%
发文量
312
审稿时长
2 months
期刊介绍: Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance. Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.
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