%0 Journal Article
%T Glycogen Synthase Kinase-3beta regulates Snail and beta-catenin during gastrin-induced migration of gastric cancer cells
%A Prajna Mishra
%A Subramanian Senthivinayagam
%A Ajay Rana
%A Basabi Rana
%J Journal of Molecular Signaling
%D 2010
%I Ubiquity Press
%R 10.1186/1750-2187-5-9
%X Our results indicate that incubation of gastric cancer cells overexpressing CCK2 receptor (AGSE cells) with G17 results in a dose and time dependent increase of GSK3¦ÂSer9 phosphorylation, indicative of an inhibition of the kinase. Pretreatment with a pharmacological inhibitor of PI3Kinase pathway (Wortmannin) was unable to antagonize G17-induced GSK3¦ÂSer9 phosphorylation, suggesting that this might involve PI3Kinase-independent pathways. Treatment with G17 was also associated with increased Snail expression, and ¦Â-catenin nuclear translocation, both of which are GSK3¦Â downstream targets. Pretreatment with a pharmacological inhibitor of GSK3¦Â (AR-A014418) augmented Snail expression and ¦Â-catenin nuclear translocation in the absence of G17, whereas overexpression of a phosphorylation deficient mutant of GSK3¦Â (S9A) abrogated Snail promoter induction. These suggested that G17 modulates Snail and ¦Â-catenin pathways via inhibiting GSK3¦Â. In addition, overexpression of GSK3¦Â wild type (WT) or S9A mutant inhibited G17-induced migration and MMP7 promoter induction. G17 studies designed following small interference RNA (siRNA)-mediated knockdown of Snail and ¦Â-catenin expression indicated a significant reduction of G-17-induced migration and MMP7 promoter induction following combined knockdown of both proteins.Our studies indicate that inhibition of GSK3¦Â is necessary to activate G17-induced migratory pathways in gastric cancer cells. Inhibition of GSK3¦Â leads to an induction of Snail expression and ¦Â-catenin nuclear translocation, both of which participate to promote G17-induced migration.Gastric cancer is the second leading cause of cancer-related deaths worldwide [1], and are often characterized as highly aggressive and unresponsive to therapy [2]. The major risk factor contributing to this disease include Helicobacter pylori (H. pylori) infection, diet as well as genetic background [3,4]. Interestingly, studies during the past two decades have also demonstrated that the
%U http://www.jmolecularsignaling.com/content/5/1/9