Open AccessTunicamycin inhibits cell proliferation and migration in hepatocellular carcinoma through suppression of CD 44s and the ERK 1/2 pathway
Author(s) -
Hou Helei,
Ge Chao,
Sun Hefen,
Li Hong,
Li Jinjun,
Tian Hua
Publication year - 2018
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13518
Subject(s) - cell migration , mapk/erk pathway , cancer research , cell growth , tunicamycin , chemistry , microbiology and biotechnology , mek inhibitor , cell , epithelial–mesenchymal transition , apoptosis , biology , phosphorylation , downregulation and upregulation , unfolded protein response , biochemistry , gene
Tunicamycin ( TM ) is an N ‐linked glycosylation ( NLG ) inhibitor with strong antitumor activity, the exact underlying molecular mechanism of which remains to be elucidated. In our previous studies, we found that TM reversed drug resistance and improved the efficacy of combination treatments for hepatocellular carcinomas ( HCC ). Here, we investigated the effects of TM on HCC cell proliferation and migration as well as the mechanism of those effects. Our results showed that TM inhibited cell proliferation and migration as well as induced apoptosis of hepatocellular carcinoma cells. TM inhibited proliferation of HCC cells by inducing cell apoptosis and cell cycle arrest at the G2/M phase. Meanwhile, TM inhibited migration of HCC cells by suppressing CD 44s‐mediated epithelial‐mesenchymal transition ( EMT ). TM inhibited migration and invasion of HCC cells by decreasing CD 44 expression and altering its glycosylation. In addition, CD 44s is involved in promoting EMT and is associated with a poor prognosis in HCC patients. Overexpression of CD 44s promoted tumor migration and activated phosphorylation of ERK 1/2 in HCC cells, whereas TM inhibited CD 44s overexpression‐associated cell migration. The ability of TM to inhibit cell migration and invasion was enhanced or reversed in CD 44s knockdown cells and cells overexpressing CD 44s, respectively. The MEK / ERK inhibitor U0126 and TM inhibited hyaluronic acid‐induced cell migration in HCC cells. Furthermore, TM inhibited exogenous transforming growth factor beta ( TGF ‐β)‐mediated EMT by an ERK 1/2‐dependent mechanism and restored the TGF ‐β‐mediated loss of E‐cadherin. In summary, our study provides evidence that TM inhibits proliferation and migration of HCC cells through inhibition of CD 44s and the ERK 1/2 signaling pathway.