Abstract
Tunicamycin is an N-linked glycosylation (NLG) inhibitor with strong anti-tumor activity, the exact underlying molecular mechanism of which remains to be elucidated. In our previous studies, we found that tunicamycin reversed drug resistance and improved the efficacy of combination treatments for hepatocellular carcinomas (HCC). Here, we investigated the effects of tunicamycin on HCC cell proliferation and migration as well as mechanism of those effects. Our results showed that tunicamycin inhibited cell proliferation and migration as well as induced apoptosis of hepatocellular carcinoma cells. Tunicamycin inhibited proliferation of HCC cells by inducing cell apoptosis and cell cycle arrest at the G2/M phase. Meanwhile, tunicamycin inhibited migration of HCC cells by suppressing CD44s-mediated epithelial–mesenchymal transition (EMT). Tunicamycin inhibited migration and invasion of HCC cells by decreasing CD44 expression and altering its glycosylation. In addition, CD44s is involved in promoting EMT and is associated with a poor prognosis in HCC patients. Overexpression of CD44s promoted tumor migration and activated phosphorylation of ERK1/2 in HCC cells, whereas tunicamycin inhibited CD44s overexpression-associated cell migration. The ability of tunicamycin to inhibit cell migration and invasion was enhanced or reversed in CD44s knockdown cells and cells overexpressing CD44s, respectively. The MEK/ERK inhibitor U126 and tunicamycin inhibited hyaluronic acid-induced cell migration in HCC cells. Furthermore, tunicamycin inhibited exogenous TGF-β-mediated EMT via an ERK1/2-dependent mechanism and restored the TGF-β–mediated loss of E-cadherin. In summary, our study provides evidence that tunicamycin inhibits proliferation and migration of HCC cells through inhibition of CD44s and the ERK1/2 signaling pathway.
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