Gastrin-releasing peptide-mediated neuroblastoma growth: A role for the PI3K/Akt pathway

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Title: Gastrin-releasing peptide-mediated neuroblastoma growth: A role for the PI3K/Akt pathway
Author: Titilope Adenike Ishola
Abstract: Neuroblastoma is the most common extracranial solid tumor in infants and children . Our lab and others have shown trophic actions of gastrin -releasing peptide (GRP ) , and its analogue bombesin (BBS ) , in neuroblastomas . Our lab also found that undifferentiated neuroblastomas express increased levels of GRP receptor (GRPR ) . Activation of the phosphatidylinositol -3 -kinase (PI3K ) /Akt pathway , a crucial regulator of cell survival , is associated with poor outcome in neuroblastomas and our lab¡¦s previous work has shown that GRPR regulates the expression of PI3K /Akt pathway components . However , the signaling mechanisms involved in this process are not clearly defined . Therefore , the objective of this project was to determine how GRP /GRPR , by way of PI3K pathway , regulates neuroblastoma growth . \r \n \r \nGRP /BBS treatment rapidly increased phosphorylation of both Akt and GSK -3ƒÒ in neuroblastoma cells . Antagonism or silencing of GRPR attenuated BBS -induced phosphorylation of Akt . PI3K inhibition also abrogated BBS -stimulated phosphorylated (p ) -Akt as well as its cell cycle targets . GRP increased G1 /S phase progression in SK -N -SH cells and BBS -mediated BrdU incorporation was blocked with a PI3K inhibitor . These findings identify PI3K /Akt as an important signaling pathway for GRP -mediated neuroblastoma cell growth . In order to determine the in vivo significance of GRP /GRPR , the effects of BBS treatment in nude mice with human neuroblastoma xenografts were assessed . BBS treatment significantly increased the growth and mediators of angiogenesis of SK -N -SH and BE (2 ) -C tumors , as well as increased p -Akt levels . A GRPR antagonist reduced BBS -stimulated tumor growth and angiogenic markers in vivo . GRP or GRPR silencing inhibited the expressions of VEGF , p -Akt , and p -mTOR in vitro . GRPR knockdown induced cell morphology changes , reduced cell size , decreased cell proliferation , and inhibited DNA synthesis , which corresponded to G2 /M cell cycle arrest . Activated Akt and its downstream regulators of protein synthesis and metabolism were also significantly downregulated by GRPR silencing . GRPR knockdown upregulated the expression of PTEN , the inhibitor of the PI3K /Akt pathway . Furthermore , silencing of GRPR or GRP suppressed anchorage -independent growth ; while GRPR overexpression resulted in soft agar colony formation , which was inhibited by a GRP -blocking antibody . In conclusion , these findings demonstrate that GRP /GRPR signaling regulates the PI3K /Akt pathway and promotes neuroblastoma growth , angiogenesis , and oncogenic properties .
URI: http : / /hdl .handle .net /2152 .3 /107
Date: 2008-12-18

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Gastrin-releasing peptide-mediated neuroblastoma growth: A role for the PI3K/Akt pathway. Doctoral dissertation, The University of Texas Medical Branch. Available electronically from http : / /hdl .handle .net /2152 .3 /107 .

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