Abstract
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.
Original language | English |
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Pages (from-to) | 927-932 |
Number of pages | 6 |
Journal | Biochimica et Biophysica Acta - General Subjects |
Volume | 1770 |
Issue number | 6 |
DOIs | |
State | Published - Jun 2007 |
Bibliographical note
Funding Information:The authors thank Karen Martin for manuscript preparation and Lan Pang for assistance with the experiments. This work was supported by grants RO1 DK61470, RO1 DK48498, RO1 CA104748 and PO1 DK35608 from the National Institutes of Health and an Institutional Research Grant (IRG-110376) from the American Cancer Society.
Keywords
- Akt
- Bombesin
- Cell cycle
- GRP
- Neuroblastoma
- PI3K
ASJC Scopus subject areas
- Biophysics
- Biochemistry
- Molecular Biology