Honokiol inhibits EMT-mediated motility and migration of human non-small cell lung cancer cells in vitro by targeting c-FLIP

• Published in: Acta pharmacologica Sinica Vol. 37; no. 12; pp. 1574 - 1586
• Main Authors: Lv, Xiao-qin, Qiao, Xin-ran, Su, Ling, Chen, Shu-zhen
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2016; Nature Publishing Group
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Autophagy - drug effects; Biomedical and Life Sciences; Biomedicine; Biphenyl Compounds - pharmacology; Carcinoma, Non-Small-Cell Lung - drug therapy; CASP8 and FADD-Like Apoptosis Regulating Protein - metabolism; Cell Line, Tumor - drug effects; Cell Movement - drug effects; EMT; Epithelial-Mesenchymal Transition - drug effects; Humans; Immunology; Internal Medicine; Lignans - pharmacology; Lung cancer; Lung Neoplasms - drug therapy; Medical Microbiology; Original; original-article; Pharmacology/Toxicology; Vaccine; 人类; 介导; 体外培养; 信号转导机制; 细胞迁移; 肺癌细胞; 运动; snail; NF-κB; N-cadherin; non-small cell lung cancer cells; Honokiol; epithelial-mesenchymal transition; Smad; c-FLIP; cancer metastasis
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/aps.2016.81

Aim： Honokiol （HNK） is a natural compound isolated from the magnolia plant with numerous pharmacological activities, including inhibiting epithelial-mesenchymal transition （EMT）, which has been proposed as an attractive target for anti-tumor drugs to prevent tumor migration. In this study we investigated the effects of HNK on EMT in human NSCLC cells in vitro and the related signaling mechanisms. Methods： TNF-α （25 ng/mL） in combination with TGF-β4 （5 ng/mL） was used to stimulate EMT of human NSCLC A549 and H460 cells. Cell proliferation was analyzed using a sulforhodamine B assay. A wound-healing assay and a transwell assay were performed to examine cell motility. Western blotting was used to detect the expression levels of relevant proteins, siRNAs were used to knock down the gene expression of c-FLIP and N-cadherin. Stable overexpression of c-FLIP L （H157-FLIP L） or Lac Z （H157-Lac Z） was also performed.Results： Treatment with TNF-α＋TGF-β1 significantly enhanced the migration of A549 and H460 ceils, increased c-FLIP, N-cadherin （a mesenchymal marker）, snail （a transcriptional modulator） and p-Smad2/3 expression, and decreased IKB levels in the cells; these changes were abrogated by co-treatment with HNK （30 pmol/L）. Further studies demonstrated that expression level of c-FLIP was highly correlated with the movement and migration of NSCLC cells, and the downstream effectors of c-FLIP signaling were NF-κB signaling and N-cadherin/snail signaling, while Smad signaling might lie upstream of c-FLIP. Conclusion： HNK inhibits EMT-mediated motility and migration of human NSCLC cells in vitro by targeting c-FLIP, which can be utilized as a promising target for cancer therapy, while HNK may become a potential anti-metastasis drug or lead compound.