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5673839 
Journal Article 
Preferential killing of PTEN-null myelomas by PI3K inhibitors through Akt pathway 
Zhang, J; Choi, Y; Mavromatis, B; Lichtenstein, A; Li, W 
2003 
1 
Oncogene
ISSN: 0950-9232
EISSN: 1476-5594 
Oncogene. 
22 
40 
6289-95. [Oncogene] 
English 
We recently reported that internal deletion of PTEN tumor suppressor gene in OPM2 and Delta47 myeloma lines led to high Akt activation. Re-expression of PTEN induced strong apoptosis and growth inhibition. To understand the biologic importance of the phosphatidylinositol 3 kinase (PI3K)/Akt activation affected by PTEN deletion, we analysed apoptosis and growth inhibition by applying PI3K inhibitors to myeloma lines and by expressing Akt constructs. The PI3K inhibitors preferentially suppressed PTEN-null myeloma growth to those expressing PTEN, indicating that PI3K activation is more critical for growth and survival of those lines with PTEN mutations than others expressing a functional PTEN gene. Since PTEN-null myeloma lines exhibited much stronger Akt activation than PTEN-expressing cells in response to insulin-like growth factor I stimulation, we determined whether Akt could be responsible for PI3K-mediated cell survival and growth of PTEN-null myeloma lines. Expression of an active Akt, but not its kinase dead mutant, reversed wortmannin- and dexamethasone-induced apoptosis and growth inhibition in PTEN-null myeloma lines, suggesting that Akt lies downstream of PI3K for PTEN-null myeloma survival and dexamethasone resistance. In summary, we have provided evidence that PTEN-null myeloma cells are stringently dependent on the PI3K/Akt activation for cell survival. These results may provide a basis to treat myeloma patients with PI3K and Akt inhibitors. 
Androstadienes/pharmacology; Antineoplastic Agents/pharmacology; Apoptosis/drug effects; Butadienes/pharmacology; Cell Division/drug effects; Cell Survival; Chromones/pharmacology; Dexamethasone/pharmacology; Enzyme Activation; Enzyme Inhibitors/pharmacology; Gene Deletion; Genes, Tumor Suppressor; Insulin-Like Growth Factor I/pharmacology; Interleukin-6/pharmacology; Morpholines/pharmacology; Multiple Myeloma/genetics/metabolism; Nitriles/pharmacology; PTEN Phosphohydrolase; Phosphatidylinositol 3-Kinases/antagonists & inhibitors; Phosphoric Monoester Hydrolases/genetics/metabolism; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins/metabolism; Proto-Oncogene Proteins c-akt; Signal Transduction; Tumor Cells, Cultured; Tumor Suppressor Proteins/genetics/metabolism; Wortmannin; 31M2U1DVID; 67763-96-6; 7S5I7G3JQL