Biseugenol (Eug) is known to antiproliferative of
cancer cells; however, to date, the antiperitoneal dissemination effects have not been studied in any mouse
cancer model. In this study,
Aryl hydrocarbon receptor (AhR) expression was associated with lymph node and distant
metastasis in patients with
gastric cancer and was correlated with clinicolpathological pattern. We evaluated the antiperitoneal dissemination potential of knockdown AhR and Biseugenol in
cancer mouse model and assessed mesenchymal characteristics. Our results demonstrate that
tumor growth, peritoneal dissemination and peritoneum or organ
metastasis implanted MKN45 cells were significantly decreased in shAhR and Biseugenol-treated mice and that endoplasmic reticulum (ER) stress was caused. Biseugenol-exposure
tumors showed acquired epithelial features such as phosphorylation of
E-cadherin,
cytokeratin-18 and loss mesenchymal signature Snail, but not
vimentin regulation. Snail expression, through AhR activation, is an epithelial-to-mesenchymal transition (EMT) determinant. Moreover, Biseugenol enhanced Calpain-10 (Calp-10) and AhR interaction results in Snail downregulation. The effect of shCalpain-10 in
cancer cells was associated with inactivation of AhR/Snail promoter binding activity. Inhibition of Calpain-10 in
gastric cancer cells by
short hairpin RNA or pharmacological inhibitor was found to effectively reduced growth ability and vessel density in vivo. Importantly, knockdown of AhR completed abrogated peritoneal dissemination. Herein, Biseugenol targeting ER stress provokes Calpain-10 activity, sequentially induces reversal of EMT and apoptosis via AhR may involve the paralleling processes. Taken together, these data suggest that Calpain-10 activation and AhR inhibition by Biseugenol impedes both gastric
tumor growth and peritoneal dissemination by inducing ER stress and inhibiting EMT.