PI3K/Akt-dependent phosphorylation of GSK3β and activation of RhoA regulate Wnt5a-induced gastric cancer cell migration

Wnt5a, a non-transforming Wnt family member, plays complicated roles in oncogenesis and cancer metastasis. However, Wnt5a signaling in gastric cancer progression remains poorly defined. In this study, we found that Wnt5a dose-dependently stimulated the migration of human gastric cancer cells (SGC-7901), with the maximal effect at 100 ng/mL, via enhancing phosphorylation of PI3K/Akt and GSK3 beta and activating RhoA. Pharmaceutical inhibition of FISK with LY294002 or Akt siRNA significantly decreased Wnt5a-induced GSK3 beta phosphorylation and consequently cell migration. Additionally, GSM beta siRNA remarkably inhibited Wnt5a-induced RhoA activation, stress fiber formation and cell migration. Analogously, pre-treatment with LiCl, which induced phosphorylation of GSK3 beta at Ser9, increased Wnt5a-induced cell migration. Finally, ectopic expression of dominant negative RhoA (N19) suppressed Wnt5a-induced cell migration. Taken together, we demonstrated for the first time that Wnt5a promoted gastric cancer cell migration via the PI3K/Akt/GSK3 beta/RhoA signaling pathway. These findings could provide a rationale for designing new therapy targeting gastric cancer metastasis. Crown Copyright (C) 2012 Published by Elsevier Inc. All rights reserved.