title: Inhibition of invasion and metastasis by DMBT, a novel trehalose derivative, through Akt/GSK-3β/β-catenin pathway in B16BL6 cells.
abstract: Invasion, either directly or via metastasis formation, is the main cause of death in cancer patients. Development of efficient anti-invasive agents is an important research challenge. 6,6'-bis (2,3-dimethoxybenzoyl)-a, a-d-trehalose (DMBT), one of brartemicin analogs, was found to be the most potent anti-invasive agent, but the underlying mechanisms are poorly understood. Our current study was to explore the effects of DMBT on invasion and metastasis in B16BL6 cells. Antiproliferation assay and trypan blue exclusion assay showed that no obvious inhibitory or cytotoxic effect of DMBT was found in B16BL6 cells. Wound healing demonstrated that DMBT could inhibit cell migration compared with the normal group. Transwell experiments showed that DMBT could significantly inhibit invasion to the reconstituted basement membrane (P<0.01). We examined the effects of lung metastasis produced by highly metastatic B16BL6 melanoma cells by using experimental metastasis models and BLI analysis. DMBT could significantly suppress lung metastasis in mice. Results from immunohistochemical staining, Western blotting and real-time PCR indicated that the chemopreventive effect of DMBT was attributed to the inhibition of the VEGF and MMP-9 through Akt/GSK-3β/β-catenin and Akt/mTOR signaling pathways. These results suggested that DMBT could be a promising lead molecule for the anti-metastasis and serve as a therapeutic agent to inhibit cancer cell invasion and metastasis.
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan 250012, China.
authors.forename: Linlin
authors.initials: L
authors.lastname: Tang
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan 250012, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Yue
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan 250012, China; Key Laboratory of Chemical Biology of Natural Products, Ministry of Education, China.
authors.forename: Yanna
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan 250012, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yao
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan 250012, China.
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan 250012, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Tian
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan 250012, China.
authors.forename: Lianping
authors.initials: L
authors.lastname: Ge
authors.affiliation: Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan 250012, China; Key Laboratory of Chemical Biology of Natural Products, Ministry of Education, China.
authors.forename: Zhaopeng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan 250012, China; Key Laboratory of Chemical Biology of Natural Products, Ministry of Education, China. Electronic address: xzyhan@sdu.edu.cn.
authors.forename: Xiuzhen
authors.initials: X
authors.lastname: Han
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014199:Trehalose / Q000031:analogs & derivatives* / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism
chemical_list: C558286:6,6'-bis(2,3-dimethoxybenzoyl)-alpha,alpha-trehalose; D000970:Antineoplastic Agents; C495267:CTNNB1 protein, mouse; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D042461:Vascular Endothelial Growth Factor A; D051176:beta Catenin; C467480:vascular endothelial growth factor A, mouse; D014199:Trehalose; D019869:Phosphatidylinositol 3-Kinases; C514862:Akt1 protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: Akt; DMBT; Invasion; Metastasis; β-Catenin