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

Abstract

PURPOSE:

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.

• Authors: Qi-Xing Tian, Zhi-Hui Zhang, Qing-Lin Ye, Shen Xu, Qian Hong, Wei-Yang Xing, Lei Chen, De-Xin Yu, De-Xiang Xu, Dong-Dong Xie
• Journal: Journal of inflammation research (J Inflamm Res) Vol. 14 Pg. 2253-2265 ( 2021) ISSN: 1178-7031 [Print] New Zealand
• PMID: 34079331 (Publication Type: Journal Article, Retracted Publication)
• Copyright: © 2021 Tian et al.