Phosphatidylinositol 3-kinase regulation of gastrin-releasing peptide-induced cell cycle progression in neuroblastoma cells
| Autor: | Dai H. Chung, Jung Hee Kang, Jingbo Qiao, B. Mark Evers, Titilope A. Ishola |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Morpholines Biophysics Biochemistry Article S Phase Glycogen Synthase Kinase 3 Neuroblastoma Phosphatidylinositol 3-Kinases Gastrin-releasing peptide Cell Line Tumor medicine PTEN Humans Enzyme Inhibitors Phosphorylation RNA Small Interfering Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway Phosphoinositide-3 Kinase Inhibitors Glycogen Synthase Kinase 3 beta biology Kinase G1 Phase PTEN Phosphohydrolase Cell cycle medicine.disease Gene Expression Regulation Neoplastic Receptors Bombesin Autocrine Communication Gastrin-Releasing Peptide Chromones biology.protein Cancer research Bombesin Signal transduction Protein Processing Post-Translational Proto-Oncogene Proteins c-akt hormones hormone substitutes and hormone antagonists Signal Transduction |
| Zdroj: | Biochimica et biophysica acta. 1770(6) |
| ISSN: | 0006-3002 |
| Popis: | Gastrin-releasing peptide (GRP), the mammalian equivalent of bombesin (BBS), is an autocrine growth factor for neuroblastoma; its receptor is up-regulated in undifferentiated neuroblastomas. Phosphatidylinositol 3-kinase (PI3K) is a critical cell survival pathway; it is negatively regulated by the PTEN tumor suppressor gene. We have recently found that poorly differentiated neuroblastomas express decreased PTEN protein levels. Moreover, overexpression of the GRP receptor, a member of the G-protein coupled receptor family, down-regulates PTEN expression, resulting in increased neuroblastoma cell growth. Therefore, we sought to determine whether GRP or BBS activates PI3K in neuroblastoma cells (BE(2)-C, LAN-1, SK-N-SH). GRP or BBS treatment rapidly increased phosphorylation of Akt and GSK-3β in neuroblastoma cells. Inhibition of GRP receptor, with antagonist GRP-H2756 or siRNA, attenuated BBS-induced phosphorylation of Akt. LY294002, a PI3K inhibitor, also abrogated BBS-stimulated phospho-Akt as well as its cell cycle targets. GRP increased G1/S phase progression in SK-N-SH cells. BBS-mediated BrdU incorporation was blocked by LY294002. Our findings identify PI3K as an important signaling pathway for GRP-mediated neuroblastoma cell growth. A novel therapy targeted at GRP/GRP receptor may prove to be an effective treatment option to inhibit PI3K in neuroblastomas. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|