Sulindac and its metabolites inhibit invasion of glioblastoma cells via down-regulation of Akt/PKB and MMP-2.
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.
Lee
Hyung-Chahn
HC
Laboratory of Cell Biology, Department of Laboratory Medicine and Clinical Pathology, Korea Cancer Center Hospital, Seoul 139-240, Korea.
Park
In-Chul
IC
Park
Myung-Jin
MJ
An
Sungkwan
S
Woo
Sang-Hyeok
SH
Jin
Hyeon-Ok
HO
Chung
Hee Yong
HY
Lee
Su-Jae
SJ
Gwak
Ho-Shin
HS
Hong
Young-Jun
YJ
Yoo
Doo-Hyun
DH
Rhee
Chang-Hun
CH
Hong
Seok-Il
SI
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects*; D005909:Glioblastoma / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D013467:Sulindac / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011518:Proto-Oncogene Proteins; D013467:Sulindac; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020778:Matrix Metalloproteinase 2