Phosphatidylinositol 3-kinase regulation of gastrin-releasing peptide-induced cell cycle progression in neuroblastoma cells

Titilope A. Ishola, Jung Hee Kang, Jingbo Qiao, B. Mark Evers, Dai H. Chung

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

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 languageEnglish
Pages (from-to)927-932
Number of pages6
JournalBiochimica et Biophysica Acta - General Subjects
Volume1770
Issue number6
DOIs
StatePublished - 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

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