Chitin synthesis inhibitors promote liver cancer cell metastasis via interfering with hypoxia-inducible factor 1α. (September 2018)

• Record Type: Journal Article
• Authors: Ning, Xia; Wang, Yue; Yan, Wei; Li, Guangke; Sang, Nan
• Is Part Of: Chemosphere. Volume 206(2018)
• Page Start: 231
• Page End: 237
• Publication Date: 2018-09
• Subjects: Chitin synthesis inhibitors (CSIs) -- Cancer cell metastasis -- Hypoxia-inducible factor 1α (HIF-1α); CSIs chitin synthesis inhibitors -- HIF-1α hypoxia-inducible factor 1α -- RLA the relative luciferase activity -- EMT epithelial-to-mesenchymal transition -- ECM extracellular matrix -- FN1 fibronectin -- MMP-2 matrix metalloproteinase-2 -- E-cad E-cadherin -- TIMP-2 tissue inhibitor of metalloproteinases-2 -- HREs hypoxia-response elements -- OP 1, 10-phenanthroline -- DMSO dimethyl sulfoxide -- HepG2 the human hepatocellular carcinoma cell line -- DMEM Dulbecco's modified Eagle's medium -- FBS fetal bovine serum -- CD-FBS charcoal/dextran-treated FBS -- PBS phosphate-buffered saline -- cDNA first-strand complementary DNA -- PPARγ peroxisome proliferator-activated receptor γ -- ERα α-estrogen receptors -- ERβ β-estrogen receptors -- AR androgen receptor -- AhR aryl hydrocarbon receptor; Pollution -- Periodicals; Pollution -- Physiological effect -- Periodicals; Environmental sciences -- Periodicals; Atmospheric chemistry -- Periodicals; 551.511
• DOI: 10.1016/j.chemosphere.2018.05.014
• Languages: English
• ISSNs: 0045-6535

Abstract

Abstracts: Chitin synthesis inhibitors (CSIs), as alternatives to conventional insecticides, have been in worldwide demand in recent years. However, little attention has been paid to the potential ecological safety and health risks of CSIs, especially their abilities to interfere with nonsexual hormone receptors such as hypoxia-inducible factor 1α (HIF-1α). In this work, we conducted a systematic study regarding the influence of CSIs on HIF-1α-related liver cancer cell metastasis. The dual-luciferase reporter gene assay revealed that two of fourteen CSIs exhibited dose-response HIF-1α agonistic activities at noncytotoxic concentrations with relative luciferase activity (RLA) values of 25.6% for diflubenzuron (DFB) and 20.9% for triflumuron (TFM). Following this result, in vitro bioassays demonstrated that both DFB and TFM stimulated HepG2 cell migration and invasion. This action was associated with the varied expression levels of genes involved in epithelial-to-mesenchymal transition (EMT) activation and extracellular matrix (ECM) degradation, such as the upregulation of fibronectin (FN1) and matrix metalloproteinase-2 (MMP-2) and the suppression of E-cadherin (E-cad) and tissue inhibitor of metalloproteinases-2 (TIMP-2). Moreover, changes in these EMT and ECM phenotype markers were dramatically blocked by a HIF-1α inhibitor (KC7F2), which further verified the involvement of HIF-1α in CSI-induced HepG2 cell metastasis. For the first time, our findings reveal that CSIs play crucial roles in promoting the metastasis of human liver cancer cells and that HIF-1α is potentially responsible for these changes. Highlights: Two of fourteen CSIs show conspicuous HIF-1α agonistic activity. HIF-1α-agonistic CSIs enhance HepG2 cell metastasis. HIF-1α participates in the CSIs-induced EMT activation and ECM degradation.