Exp Mol Med.  2005 Oct;37(5):391-398.

PTEN/MMAC1 enhances the growth inhibition by anticancer drugs with downregulation of IGF-II expression in gastric cancer cells

• Hwang PH
• Kim SY
• Lee JC
• Kim SJ
• Yi HK
• Lee DY

Abstract

PTEN/MMAC1 is a tumor suppressor gene that is mutated in a variety of advanced and metastatic cancers. Its major function is likely to be the phosphatase activity that regulates the phosphotidylinositol (PI)3-kinase/ Akt pathway. On the other hand, IGF system plays an important role in cell proliferation and cell survival via PI3-kinase/Akt and mitogen-activated protein kinase pathways in many cancer cells. To evaluate effect of PTEN on cell growth and IGF system in gastric cancer, human gastric adenocarcinoma cells (SNU-5 & -216) were transfected with human PTEN cDNA. Those PTEN- transfected gastric cancer cells had a lower proliferation rate than the pcDNA3-transfected cells. PTEN overexpression induced a profound decrease in the IGF-II and IGF-IR expression levels, and downregulation of IGF-II expression by PTEN was mediated through the regulation of the IGF-II promoter. In addition, a PI3-kinase inhibitor, LY294002, induced the downregulation of IGF-II expression. The PTEN-overexpressing SUN-5 and -216 cells were more sensitive to death induced by etoposide and adriamycin that induce DNA damage than the pcDNA3-transfected cells. These findings suggest that PTEN suppresses the cell growth through modulation of IGF system and sensitizing cancer cells to cell death by anticancer drugs.

Keyword

genes, tumor supprressor; insulin-like growth factor II; receptor, IGF type I; stomach neoplasms

MeSH Terms

Antineoplastic Agents/*pharmacology
Cell Line, Tumor
Cell Proliferation/drug effects
*Down-Regulation
Humans
Insulin-Like Growth Factor II/*genetics/*metabolism
PTEN Phosphohydrolase/genetics/*metabolism
Receptor, IGF Type 1/genetics/metabolism
Research Support, Non-U.S. Gov't
Stomach Neoplasms/*genetics/metabolism/*pathology