title: The novel Aryl hydrocarbon receptor inhibitor biseugenol inhibits gastric tumor growth and peritoneal dissemination.
abstract: 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.
authors.affiliation: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.
authors.forename: De-Wei
authors.initials: DW
authors.lastname: Lai
authors.affiliation: Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan. Contributed equally to first author.
authors.forename: Shing-Hwa
authors.initials: SH
authors.lastname: Liu
authors.affiliation: Department of Dermatology, Emory University School of Medicine, Winship Cancer Institute, Atlanta Veterans Administration Health Center, Atlanta, Georgia, USA.
authors.forename: Anna Isabella
authors.initials: AI
authors.lastname: Karlsson
authors.affiliation: Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan. Contributed equally to first author.
authors.forename: Wen-Jane
authors.initials: WJ
authors.lastname: Lee
authors.affiliation: Department of Nuclear Medicine, Kuang Tien General Hospital, Taichung, Taiwan.
authors.forename: Keh-Bin
authors.initials: KB
authors.lastname: Wang
authors.affiliation: Department of Nuclear Medicine, Kuang Tien General Hospital, Taichung, Taiwan.
authors.forename: Yi-Ching
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Institute of Nuclear Energy Research, Atomic Energy Council, Longtan, Taoyua, Taiwan.
authors.forename: Chin-Chang
authors.initials: CC
authors.lastname: Shen
authors.affiliation: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Sheng-Mao
authors.initials: SM
authors.lastname: Wu
authors.affiliation: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Chia-Yu
authors.initials: CY
authors.lastname: Liu
authors.affiliation: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Hsing-Ru
authors.initials: HR
authors.lastname: Tien
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Yen-Chun
authors.initials: YC
authors.lastname: Peng
authors.affiliation: Department of Pathology and Laboratory Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Yee-Jee
authors.initials: YJ
authors.lastname: Jan
authors.affiliation: Division of Colorectal Surgery, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Te-Hsin
authors.initials: TH
authors.lastname: Chao
authors.affiliation: Department and Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan. Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Keng-Hsin
authors.initials: KH
authors.lastname: Lan
authors.affiliation: Department of Dermatology, Emory University School of Medicine, Winship Cancer Institute, Atlanta Veterans Administration Health Center, Atlanta, Georgia, USA.
authors.forename: Jack L
authors.initials: JL
authors.lastname: Arbiser
authors.affiliation: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan. Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan. Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Meei-Ling
authors.initials: ML
authors.lastname: Sheu
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D010534:Peritoneal Neoplasms / Q000556:secondary*; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D013274:Stomach Neoplasms / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018336:Receptors, Aryl Hydrocarbon