PTEN-induction in U251 glioma cells decreases the expression of insulin-like growth factor binding protein-2.
PTEN is a tumor suppressor gene whose loss of function is observed in approximately 40-50% of human cancers. Although insulin-like growth factor binding protein-2 (IGFBP-2) was classically described as a growth inhibitor, multiple recent reports have shown an association of overexpression and/or high serum levels of IGFBP-2 with poor prognosis of several malignancies, including gliomas. Using an inducible PTEN expression system in the PTEN-null glioma cell line U251, we demonstrate that PTEN-induction is associated with reduced proliferation, increased apoptosis, and a substantial reduction of the high levels of IGFBP-2 expression. The PTEN-induced decrease in IGFBP-2 expression could be mimicked with the PI3-kinase inhibitor LY294002, indicating that the lipid phosphatase activity of PTEN is responsible for the observed effect. However, the rapamycin analog CCI-779 did not affect IGFBP-2 expression, suggesting that the PTEN-induced decrease in IGFBP-2 expression is not attributable to decreased mTOR signalling. Recombinant human IGFBP-2 was unable to rescue U251-PTEN cells from the antiproliferative effects of PTEN, and IGFBP-2 siRNA did not affect the IGF-dependent or -independent growth of this cell line. These results suggest that the clinical data linking IGFBP-2 expression to poor prognosis may arise, at least in part, because high levels of IGFBP-2 expression correlate with loss of function of PTEN, which is well known to lead to aggressive behavior of gliomas. Our results motivate translational research regarding the relationship between IGFBP-2 expression and loss of function of PTEN.
Levitt
Randy J
RJ
Lady Davis Institute for Medical Research, Jewish General Hospital, Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, Que., Canada.
Georgescu
Maria-Magdalena
MM
Pollak
Michael
M
D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004790:Enzyme Induction; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000096:biosynthesis*; D009025:Morpholines / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
D002867:Chromones; D018971:Insulin-Like Growth Factor Binding Protein 2; D009025:Morpholines; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases; D034741:RNA, Small Interfering; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C401859:temsirolimus; C546842:MTOR protein, human