PTEN/MMAC1 overexpression decreases insulin-like growth factor-I-mediated protection from apoptosis in neuroblastoma cells

Insulin-like growth factor I (IGF-I) protects cells from apoptosis primaril y through the action of phosphatidylinositol-3 kinase and the downstream se rine/threonine kinase Akt, The PTEN gene product, a protein which dephospho rylates phosphatidylinositol lipids, prevents activation of Akt and regulat es several cellular functions, including cell cycle progression, cell migra tion, and survival from apoptosis, In this study, PTEN overexpression decre ases IGF-l-induced Akt activity, enhances serum withdrawal-induced apoptosi s, and decreases IGF-I protection and cell growth in SHEP cells. The PTEN l ipid phosphatase mutant G129E fails to inhibit IGF-1-stimulated Akt activit y and protection from apoptosis. The C124S mutation, which abolishes both l ipid and protein phosphatase activity, fails to inhibit Akt activity and IG F-I protection against hyperosmotic-induced apoptosis but still inhibits gr owth and IGF-I protection against serum withdrawal-induced apoptosis. These data suggest a role for PTEN in modulating the effect of IGF-I on Akt acti vity, neuroblastoma cell growth, and protection against apoptotic stimuli.