title: Synthetic triterpenoids inhibit GSK3β activity and localization and affect focal adhesions and cell migration.
abstract: Synthetic triterpenoids are a class of anti-cancer compounds that target many cellular functions, including apoptosis and cell growth in both cell culture and animal models. We have shown that triterpenoids inhibit cell migration in part by interfering with Arp2/3-dependent branched actin polymerization in lamellipodia (To et al., 2010). Our current studies reveal that Glycogen Synthase Kinase 3 beta (GSK3β), a kinase that regulates many cellular processes, including cell adhesion dynamics, is a triterpenoid-binding protein. Furthermore, triterpenoids were observed to inhibit GSK3β activity and increase cellular focal adhesion size. To further examine whether these effects on focal adhesions in triterpenoid-treated cells were GSK3β-dependent, GSK3β inhibitors (lithium chloride and SB216763) were used to examine cell adhesion and morphology as well as cell migration. Our results showed that GSK3β inhibitors also altered cell adhesion sizes. Moreover, these inhibitors blocked cell migration and displaced proteins at the leading edge of migrating cells, consistent with what was observed in triterpenoid-treated cells. Therefore, the triterpenoids may affect cell migration via a mechanism that targets and alters the activity and localization of GSK3β.
authors.affiliation: Department of Physiology and Pharmacology, Western University, London, ON, Canada.
authors.forename: Ciric
authors.initials: C
authors.lastname: To
authors.affiliation: Department of Anatomy and Cell Biology, Western University, London, ON, Canada; Robarts Research Institute, Western University, London, ON, Canada.
authors.forename: Ashbeel
authors.initials: A
authors.lastname: Roy
authors.affiliation: Department of Physiology and Pharmacology, Western University, London, ON, Canada.
authors.forename: Eddie
authors.initials: E
authors.lastname: Chan
authors.affiliation: Department of Physiology and Pharmacology, Western University, London, ON, Canada; Department of Anatomy and Cell Biology, Western University, London, ON, Canada; Robarts Research Institute, Western University, London, ON, Canada.
authors.forename: Marco A M
authors.initials: MAM
authors.lastname: Prado
authors.affiliation: Department of Physiology and Pharmacology, Western University, London, ON, Canada. Electronic address: john.diguglielmo@schulich.uwo.ca.
authors.forename: Gianni M
authors.initials: GM
authors.lastname: Di Guglielmo
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D002465:Cell Movement / Q000187:drug effects*; D005347:Fibroblasts / Q000378:metabolism; D022001:Focal Adhesions / Q000187:drug effects* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D021381:Protein Transport; D051381:Rats
chemical_list: C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; C116817:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; D007093:Imidazoles; D007211:Indoles; D008301:Maleimides; C417521:SB 216763; D009828:Oleanolic Acid; D000071679:Glycogen Synthase Kinase 3 beta; D018021:Lithium Chloride
keywords: 2-cyano 3,12-dioxooleana-1,9 (11)-dien-28-oic acid; Cell migration; Focal adhesions; Glycogen synthase kinase 3 beta