The novel Aryl hydrocarbon receptor inhibitor biseugenol inhibits gastric tumor growth and peritoneal dissemination
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De-Wei Lai1, Shing-Hwa Liu2,*, Anna Isabella Karlsson3, Wen-Jane Lee4,*, Keh-Bin Wang5, Yi-Ching Chen5, Chin-Chang Shen6, Sheng-Mao Wu1, Chia-Yu Liu1, Hsing-Ru Tien1, Yen-Chun Peng7, Yee-Jee Jan8, Te-Hsin Chao9, Keng-Hsin Lan10,11, Jack L. Arbiser3 and Meei-Ling Sheu1,4,12
1 Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
2 Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
3 Department of Dermatology, Emory University School of Medicine, Winship Cancer Institute, Atlanta Veterans Administration Health Center, Atlanta, Georgia, USA
4 Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
5 Department of Nuclear Medicine, Kuang Tien General Hospital, Taichung, Taiwan
6 Institute of Nuclear Energy Research, Atomic Energy Council, Longtan, Taoyua, Taiwan
7 Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
8 Department of Pathology and Laboratory Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
9 Division of Colorectal Surgery, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan
10 Department and Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan
11 Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
12 Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan
* These authors contributed equally to first author
Meei-Ling Sheu, email:
Jack L. Arbiser, email:
Keywords: ER stress, Calpain-10, AhR, Snail, EMT
Received: April 23, 2014 Accepted: August 03, 2014 Published: August 04, 2014
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.
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