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Sulindac and its metabolites inhibit invasion of glioblastoma cells via down-regulation of Akt/PKB and MMP-2
- 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.
- Subjects :
- Down-Regulation
Protein Serine-Threonine Kinases
Pharmacology
Biochemistry
chemistry.chemical_compound
Sulindac
Cell Line, Tumor
Proto-Oncogene Proteins
medicine
Humans
Neoplasm Invasiveness
LY294002
Phosphorylation
Molecular Biology
Protein kinase B
PI3K/AKT/mTOR pathway
Chemistry
Kinase
Anti-Inflammatory Agents, Non-Steroidal
Cell Biology
Cell culture
Matrix Metalloproteinase 2
Signal transduction
Glioblastoma
Proto-Oncogene Proteins c-akt
medicine.drug
Subjects
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