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Sulindac and its metabolites inhibit invasion of glioblastoma cells via down-regulation of Akt/PKB and MMP-2

Authors :
Ho-Shin Gwak
Seok-Il Hong
Young Jun Hong
Sungkwan An
Su Jae Lee
Doo-Hyun Yoo
Chang-Hun Rhee
Hyeon-Ok Jin
Myung-Jin Park
Sang-Hyeok Woo
Hyung-Chahn Lee
Hee Yong Chung
In-Chul Park
Source :
Journal of Cellular Biochemistry. 94:597-610
Publication Year :
2005
Publisher :
Wiley, 2005.

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.

Details

ISSN :
10974644 and 07302312
Volume :
94
Database :
OpenAIRE
Journal :
Journal of Cellular Biochemistry
Accession number :
edsair.doi.dedup.....bd338676ae4a1775f0ddc038292968d5
Full Text :
https://doi.org/10.1002/jcb.20312