Melatonin Inhibits Migration and Invasion in LPS-Stimulated and -Unstimulated Prostate Cancer Cells Through Blocking Multiple EMT-Relative Pathways

Qi-Xing Tian,1,* Zhi-Hui Zhang,1,* Qing-Lin Ye,1 Shen Xu,1 Qian Hong,1 Wei-Yang Xing,1 Lei Chen,1 De-Xin Yu,1 De-Xiang Xu,2,3 Dong-Dong Xie1 1Department of Urology, Second Affiliated Hospital, Anhui Medical University, Hefei, 230601, People’s Republic of China; 2Department of Toxicology, A...

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Autores principales:	Tian QX, Zhang ZH, Ye QL, Xu S, Hong Q, Xing WY, Chen L, Yu DX, Xu DX, Xie DD
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2021
Materias:	-catenin emt lipopolysaccharide melatonin prostate cancer Pathology RB1-214 Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/5e05331425ea4ef5afa2970102c3405e
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spelling	oai:doaj.org-article:5e05331425ea4ef5afa2970102c3405e2021-12-02T16:51:44ZMelatonin Inhibits Migration and Invasion in LPS-Stimulated and -Unstimulated Prostate Cancer Cells Through Blocking Multiple EMT-Relative Pathways1178-7031https://doaj.org/article/5e05331425ea4ef5afa2970102c3405e2021-05-01T00:00:00Zhttps://www.dovepress.com/melatonin-inhibits-migration-and-invasion-in-lps-stimulated-and--unsti-peer-reviewed-fulltext-article-JIRhttps://doaj.org/toc/1178-7031Qi-Xing Tian,1,* Zhi-Hui Zhang,1,* Qing-Lin Ye,1 Shen Xu,1 Qian Hong,1 Wei-Yang Xing,1 Lei Chen,1 De-Xin Yu,1 De-Xiang Xu,2,3 Dong-Dong Xie1 1Department of Urology, Second Affiliated Hospital, Anhui Medical University, Hefei, 230601, People’s Republic of China; 2Department of Toxicology, Anhui Medical University, Hefei, 230032, People’s Republic of China; 3Laboratory of Environmental Toxicology, Anhui Medical University, Hefei, 230032, People’s Republic of China*These authors contributed equally to this workCorrespondence: De-Xiang XuDepartment of Toxicology, Anhui Medical University, Hefei, 230032, People’s Republic of ChinaTel +86 138 6674 1832Email xudex@126.comDong-Dong XieDepartment of Urology, Second Affiliated Hospital, Anhui Medical University, Hefei, 230601, People’s Republic of ChinaTel +86 138 6670 0010Email xiedd_urology@163.comPurpose: Gram-negative bacteria are usually found in prostate cancer (PCa) tissues. This study aims to investigate the role of lipopolysaccharide (LPS), a glycolipid compound found in the outer membrane of gram-negative bacteria, on the migration and invasion of PCa cells, and to evaluate the protective effect of melatonin.Materials and Methods: DU145, PC-3 and LNCaP cells were incubated with LPS in the presence or absence of melatonin. Wound healing and Transwell assays were used to analyze migration and invasion of PCa cells. RT-PCR and Western blotting were used to assess the mRNA and protein levels, respectively. Co-IP was used to analyze β-catenin ubiquitination.Results: Our results showed that LPS promoted migration and invasion of PCa cells. In addition, LPS stimulated inflammatory reaction and induced epithelial–mesenchymal transition (EMT) in PCa cells by activating several TLR4 downstream pathways. Specifically, LPS promoted NF-κB/IL-6/STAT3 signal transduction. In addition, LPS upregulated phosphorylation levels of cytoplasmic AKTSer473 and GSK-3βSer9. Moreover, LPS induced phosphorylation of GSK-3βSer9 in the “disruption complex”, and then inhibited phosphorylation and ubiquitination of cytoplasmic β-catenin, leading to β-catenin nuclear translocation. Interestingly, melatonin inhibited invasion and migration not only in LPS-stimulated but also in LPS-unstimulated PCa cells. Melatonin suppressed PCa cells migration and invasion by blocking EMT mediated by IL-6/STAT3, AKT/GSK-3β and β-catenin pathways.Conclusion: This study provides evidence that melatonin inhibits migration and invasion through blocking multiple TLR4 downstream EMT-associated pathways both in LPS-stimulated and -unstimulated PCa cells. Our results provide new insights into the role of bacterial infection in PCa metastasis and a potential therapeutic agent.Keywords: β-catenin, EMT, lipopolysaccharide, melatonin, prostate cancerTian QXZhang ZHYe QLXu SHong QXing WYChen LYu DXXu DXXie DDDove Medical Pressarticle-cateninemtlipopolysaccharidemelatoninprostate cancerPathologyRB1-214Therapeutics. PharmacologyRM1-950ENJournal of Inflammation Research, Vol Volume 14, Pp 2253-2265 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	-catenin emt lipopolysaccharide melatonin prostate cancer Pathology RB1-214 Therapeutics. Pharmacology RM1-950
spellingShingle	-catenin emt lipopolysaccharide melatonin prostate cancer Pathology RB1-214 Therapeutics. Pharmacology RM1-950 Tian QX Zhang ZH Ye QL Xu S Hong Q Xing WY Chen L Yu DX Xu DX Xie DD Melatonin Inhibits Migration and Invasion in LPS-Stimulated and -Unstimulated Prostate Cancer Cells Through Blocking Multiple EMT-Relative Pathways
description	Qi-Xing Tian,1,* Zhi-Hui Zhang,1,* Qing-Lin Ye,1 Shen Xu,1 Qian Hong,1 Wei-Yang Xing,1 Lei Chen,1 De-Xin Yu,1 De-Xiang Xu,2,3 Dong-Dong Xie1 1Department of Urology, Second Affiliated Hospital, Anhui Medical University, Hefei, 230601, People’s Republic of China; 2Department of Toxicology, Anhui Medical University, Hefei, 230032, People’s Republic of China; 3Laboratory of Environmental Toxicology, Anhui Medical University, Hefei, 230032, People’s Republic of China*These authors contributed equally to this workCorrespondence: De-Xiang XuDepartment of Toxicology, Anhui Medical University, Hefei, 230032, People’s Republic of ChinaTel +86 138 6674 1832Email xudex@126.comDong-Dong XieDepartment of Urology, Second Affiliated Hospital, Anhui Medical University, Hefei, 230601, People’s Republic of ChinaTel +86 138 6670 0010Email xiedd_urology@163.comPurpose: Gram-negative bacteria are usually found in prostate cancer (PCa) tissues. This study aims to investigate the role of lipopolysaccharide (LPS), a glycolipid compound found in the outer membrane of gram-negative bacteria, on the migration and invasion of PCa cells, and to evaluate the protective effect of melatonin.Materials and Methods: DU145, PC-3 and LNCaP cells were incubated with LPS in the presence or absence of melatonin. Wound healing and Transwell assays were used to analyze migration and invasion of PCa cells. RT-PCR and Western blotting were used to assess the mRNA and protein levels, respectively. Co-IP was used to analyze β-catenin ubiquitination.Results: Our results showed that LPS promoted migration and invasion of PCa cells. In addition, LPS stimulated inflammatory reaction and induced epithelial–mesenchymal transition (EMT) in PCa cells by activating several TLR4 downstream pathways. Specifically, LPS promoted NF-κB/IL-6/STAT3 signal transduction. In addition, LPS upregulated phosphorylation levels of cytoplasmic AKTSer473 and GSK-3βSer9. Moreover, LPS induced phosphorylation of GSK-3βSer9 in the “disruption complex”, and then inhibited phosphorylation and ubiquitination of cytoplasmic β-catenin, leading to β-catenin nuclear translocation. Interestingly, melatonin inhibited invasion and migration not only in LPS-stimulated but also in LPS-unstimulated PCa cells. Melatonin suppressed PCa cells migration and invasion by blocking EMT mediated by IL-6/STAT3, AKT/GSK-3β and β-catenin pathways.Conclusion: This study provides evidence that melatonin inhibits migration and invasion through blocking multiple TLR4 downstream EMT-associated pathways both in LPS-stimulated and -unstimulated PCa cells. Our results provide new insights into the role of bacterial infection in PCa metastasis and a potential therapeutic agent.Keywords: β-catenin, EMT, lipopolysaccharide, melatonin, prostate cancer
format	article
author	Tian QX Zhang ZH Ye QL Xu S Hong Q Xing WY Chen L Yu DX Xu DX Xie DD
author_facet	Tian QX Zhang ZH Ye QL Xu S Hong Q Xing WY Chen L Yu DX Xu DX Xie DD
author_sort	Tian QX
title	Melatonin Inhibits Migration and Invasion in LPS-Stimulated and -Unstimulated Prostate Cancer Cells Through Blocking Multiple EMT-Relative Pathways
title_short	Melatonin Inhibits Migration and Invasion in LPS-Stimulated and -Unstimulated Prostate Cancer Cells Through Blocking Multiple EMT-Relative Pathways
title_full	Melatonin Inhibits Migration and Invasion in LPS-Stimulated and -Unstimulated Prostate Cancer Cells Through Blocking Multiple EMT-Relative Pathways
title_fullStr	Melatonin Inhibits Migration and Invasion in LPS-Stimulated and -Unstimulated Prostate Cancer Cells Through Blocking Multiple EMT-Relative Pathways
title_full_unstemmed	Melatonin Inhibits Migration and Invasion in LPS-Stimulated and -Unstimulated Prostate Cancer Cells Through Blocking Multiple EMT-Relative Pathways
title_sort	melatonin inhibits migration and invasion in lps-stimulated and -unstimulated prostate cancer cells through blocking multiple emt-relative pathways
publisher	Dove Medical Press
publishDate	2021
url	https://doaj.org/article/5e05331425ea4ef5afa2970102c3405e
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Melatonin Inhibits Migration and Invasion in LPS-Stimulated and -Unstimulated Prostate Cancer Cells Through Blocking Multiple EMT-Relative Pathways

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