Gastrin-releasing peptide (GRP) activates phosphatidylinositol 3-kinase (PI3-K)/Akt, an important cell survival signaling pathway, to stimulate growth of various cell types. Transforming growth factor (TGF) superfamily ligands activate intracellular Smad signaling to regulate cell growth, differentiation and apoptosis; dysregulation of the TGF-β/Smad pathway has been noted in cancer cells. Therefore, we sought to determine whether a potential cross-talk exists between the TGF-β/Smad and PI3-K pathways in the regulation of neuroblastoma cell growth. Increased Smad DNA binding was noted in SK-N-SH human neuroblastoma cells when treated with LY294002, an inhibitor of PI3-K, by transcription factor/DNA array analysis and electrophoretic mobility shift assay. LY294002 treatment resulted in Smad2 accumulation in the nuclei and an increased Smad binding element (SBE)-luciferase activity. These findings were corroborated by co-transfection with pCGNN-Δp85 plasmid, which expresses a PI3-K mutant p85 subunit. In contrast, GRP treatment decreased Smad binding activity in neuroblastoma cells. Our findings demonstrate that the PI3-K pathway negatively regulates TGF-β/Smad signaling in neuroblastoma cells. GRP-induced activation of PI3-K, resulting in neuroblastoma cell growth promotion, is potentiated by down-regulation of TGF-β/Smad signaling.
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|Published - Oct 28 2006
Bibliographical noteFunding Information:
The authors thank Karen Martin for manuscript preparation. This work was supported by grants RO1 DK61470, RO1 DK48498, RO1 CA104748 and PO1 DK35608 from the National Institutes of Health.
ASJC Scopus subject areas
- Cancer Research