Impact of PTEN on the expression of insulin-like growth factors (IGFs) and IGF-binding proteins in human gastric adenocarcinoma cells

Biochem Biophys Res Commun. 2005 May 13;330(3):760-7. doi: 10.1016/j.bbrc.2005.03.045.

Abstract

PTEN is a tumor suppressor gene that is frequently mutated or deleted in a variety of human cancers including human gastric cancer. PTEN functions primarily as a lipid phosphatase and plays a key role in the regulation of the PI3 kinase/Akt pathway, thereby modulating cell proliferation and cell survival. On the other hand, the IGF system plays an important role in cell proliferation and cell survival via the PI3 kinase/Akt and MAP kinase pathways in many cancer cells. To characterize the impact of PTEN on the IGF-IGFR-IGFBP axis in gastric cancer, we overexpressed PTEN using an adenovirus gene transfer system in human gastric adenocarcinoma cells, SNU-484 and SNU-663, which lack PTEN. Overexpression of PTEN inhibited serum-induced as well as IGF-I-induced cell proliferation as compared to control cells. PTEN overexpression resulted in a significant decrease in the expression of IGF-I, -II, and IGF-IR. Interestingly, amongst the six IGFBPs, only IGFBP-3 was upregulated by PTEN, whereas IGFBP-4 and -6 were reduced. The IGFBP-3 promoter activity assay and Western immunoblotting demonstrate that PTEN regulates IGFBP-3 at the transcriptional level. In addition, the PI3 kinase inhibitor, LY294002, upregulates IGFBP-3 expression but downregulates IGF-I and IGF-II, indicating that PTEN controls IGFBP-3 and IGFs by an Akt-dependent pathway. These findings suggest that PTEN may inhibit antiapoptotic IGF actions not only by blocking the IGF-IGFR-induced Akt activity, but also by regulating expression of components of the IGF system, in particular, upregulation of IGFBP-3, which is known to exert antiproliferative effects through IGF-dependent and IGF-independent mechanisms in cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / pathology
  • Adenocarcinoma / virology
  • Adenoviridae / genetics
  • Cell Line, Tumor
  • Cell Proliferation
  • Chromones / pharmacology
  • Down-Regulation
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Insulin-Like Growth Factor Binding Protein 3 / genetics
  • Insulin-Like Growth Factor Binding Protein 3 / metabolism
  • Insulin-Like Growth Factor Binding Proteins / metabolism*
  • Insulin-Like Growth Factor I / genetics
  • Insulin-Like Growth Factor I / metabolism*
  • Insulin-Like Growth Factor II / genetics
  • Insulin-Like Growth Factor II / metabolism*
  • Morpholines / pharmacology
  • PTEN Phosphohydrolase
  • Phosphatidylinositol 3-Kinases / pharmacology
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphoric Monoester Hydrolases / genetics
  • Phosphoric Monoester Hydrolases / metabolism*
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Receptor, IGF Type 1 / genetics
  • Receptor, IGF Type 1 / metabolism
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / metabolism*
  • Stomach Neoplasms / pathology
  • Stomach Neoplasms / virology
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Up-Regulation

Substances

  • Chromones
  • Insulin-Like Growth Factor Binding Protein 3
  • Insulin-Like Growth Factor Binding Proteins
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Tumor Suppressor Proteins
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Insulin-Like Growth Factor I
  • Insulin-Like Growth Factor II
  • Receptor, IGF Type 1
  • AKT1 protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Phosphoric Monoester Hydrolases
  • PTEN Phosphohydrolase
  • PTEN protein, human