Korean J Pediatr.  2004 Aug;47(8):884-891.

The Tumor Suppressor Function of PTEN/MMAC1 through the Regulation of IGFs and IGFBPs

• Yi HK
• Hwang DJ
• Kim SY
• Lee DY
• Hwang PH

Abstract

PURPOSE
PTEN/MMAC1, a novel tumor suppressor gene, is mutated in a variety of advanced and metastatic cancers. It acts as a phosphatase, and thereby, regulates the PI-3 kinase/Akt pathway. In this study, we examined to evaluate the new function of anti-tumor effects of PTEN/MMAC1 through the regulation of the IGFs-IGFBPs in gastric cancer cells.
METHODS
PTEN/MMAC1 was expressed in an adenovirus-mediated gene delivery system and introduced into gastric cancer cells(SNU-484 & SNU-668) in vitro. The effect of cell growth and the expression of IGFs and IGFBPs after Ad/PTEN infection was analyzed by MTT assay, RT-PCR and Western immunoblot.
RESULTS
Ad/PTEN infected cells were inhibited in cell growth compared with moak cells and Ad/ LacZ infected cells. Overexpression of PTEN/MMAC1 induced decrease in expression of IGF-I, -II and IGF-I receptors which are known as growth prompt molecules in a variety of cancers. Of the six IGFBPs, the expressions of IGFBP-4 and IGFBP-6 were decreased in Ad/PTEN infected cells. In contrast, IGFBP-3 expression was markedly increased by up to 3-fold in Ad/PTEN infected cells. Overexpression of PTEN/MMAC1 inhibited the activation of Akt/PKB pathway, but had no effect on the MAPK pathway.
CONCLUSION
These findings suggest that the tumor suppressor function of PTEN/MMAC1 is, at least in part, mediated through the down-regulation of IGF-I abd IGF-II, and up-regulation of IGFBP-3 in gastric cancer cells by the inhibition of PI-3 kinase pathway.

Keyword

Genes; Tumor suppressor; Insulin-like growth factor I; Insulin-like growth factor II; Insulin-like growth-factor-binding proteins; Phosphatidylinositol 3-kinase; Stomach neoplasms

MeSH Terms

Blotting, Western
Down-Regulation
Gene Transfer Techniques
Genes, Tumor Suppressor
Insulin-Like Growth Factor Binding Protein 3
Insulin-Like Growth Factor Binding Protein 4
Insulin-Like Growth Factor Binding Protein 6
Insulin-Like Growth Factor Binding Proteins*
Insulin-Like Growth Factor I
Insulin-Like Growth Factor II
Phosphatidylinositol 3-Kinase
Phosphatidylinositol 3-Kinases
Receptor, IGF Type 1
Stomach Neoplasms
Up-Regulation
Insulin-Like Growth Factor Binding Protein 3
Insulin-Like Growth Factor Binding Protein 4
Insulin-Like Growth Factor Binding Protein 6
Insulin-Like Growth Factor Binding Proteins
Insulin-Like Growth Factor I
Insulin-Like Growth Factor II
Phosphatidylinositol 3-Kinase
Phosphatidylinositol 3-Kinases
Receptor, IGF Type 1