Inhibition of transforming growth factor-β/Smad signaling by phosphatidylinositol 3-kinase pathway

Jingbo Qiao, Junghee Kang, Tien C. Ko, B. Mark Evers, Dai H. Chung

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


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.

Original languageEnglish
Pages (from-to)207-214
Number of pages8
JournalCancer Letters
Issue number2
StatePublished - Oct 28 2006

Bibliographical note

Funding 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.


  • GRP
  • Neuroblastoma
  • PI3-K
  • Smad
  • TGF-β

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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