Abstract
Non‐steroidal anti‐inflammatory drug (NSAID), sulindac has chemopreventive and anti‐tumorigenic properties, however, the molecular mechanism of this inhibitory action has not been clearly defined. The Akt/protein kinase B, serine/threonine kinase is well known as an important mediator of many cell survival signaling pathways. In the present study, we demonstrate that down‐regulation of Akt is a major effect of anti‐invasiveness property of sulindac and its metabolites in glioblastoma cells. Myristoylated Akt (MyrAkt) transfected U87MG glioblastoma cells showed increase invasiveness, whereas DN‐Akt transfected cells showed decrease invasiveness indicating that Akt potently promoted glioblastoma cell invasion. MMP‐2 promoter and enzyme activity were up‐regulated in Akt kinase activity dependent manner. Sulindac and its metabolites down‐regulated Akt phosphorylation, inhibited MMP‐2 production, and significantly inhibited invasiveness of human glioblastoma cells. In addition, sulindac and LY294002, a selective inhibitor of phosphoinositide 3‐kinase (PI3K), synergistically inhibited the invasion of glioblastoma cells. Furthermore, only celecoxib showed Akt phosphorylation reduction and an anti‐invasivness in glioblastoma cells, whereas aspirin, ketoprofen, ketorolac, and naproxen did not. In conclusion, our results provide evidence that down‐regulation of Akt pathway and MMP‐2 may be one of the mechanisms by which sulindac and its metabolites inhibit glioblastoma cell invasion. © 2004 Wiley‐Liss, Inc.