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
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / genetics
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Adenocarcinoma / metabolism*
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Adenocarcinoma / pathology
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Adenocarcinoma / virology
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Adenoviridae / genetics
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Cell Line, Tumor
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Cell Proliferation
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Chromones / pharmacology
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Down-Regulation
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Gene Expression Regulation, Neoplastic*
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Humans
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Insulin-Like Growth Factor Binding Protein 3 / genetics
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Insulin-Like Growth Factor Binding Protein 3 / metabolism
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Insulin-Like Growth Factor Binding Proteins / metabolism*
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Insulin-Like Growth Factor I / genetics
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Insulin-Like Growth Factor I / metabolism*
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Insulin-Like Growth Factor II / genetics
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Insulin-Like Growth Factor II / metabolism*
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Morpholines / pharmacology
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PTEN Phosphohydrolase
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Phosphatidylinositol 3-Kinases / pharmacology
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Phosphoinositide-3 Kinase Inhibitors
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Phosphoric Monoester Hydrolases / genetics
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Phosphoric Monoester Hydrolases / metabolism*
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Phosphorylation
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Protein Kinase Inhibitors / pharmacology
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Receptor, IGF Type 1 / genetics
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Receptor, IGF Type 1 / metabolism
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Stomach Neoplasms / genetics
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Stomach Neoplasms / metabolism*
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Stomach Neoplasms / pathology
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Stomach Neoplasms / virology
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
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Up-Regulation
Substances
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Chromones
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Insulin-Like Growth Factor Binding Protein 3
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Insulin-Like Growth Factor Binding Proteins
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Morpholines
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Tumor Suppressor Proteins
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Insulin-Like Growth Factor I
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Insulin-Like Growth Factor II
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Receptor, IGF Type 1
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Phosphoric Monoester Hydrolases
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PTEN Phosphohydrolase
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PTEN protein, human