Preferential killing of PTEN-null myelomas by PI3K inhibitors through Akt pathway.
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.
D000730:Androstadienes / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002070:Butadienes / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival; D002867:Chromones / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D051059:PTEN Phosphohydrolase; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*; D000077191:Wortmannin
D000730:Androstadienes; D000970:Antineoplastic Agents; D002070:Butadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D009025:Morpholines; D009570:Nitriles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D007334:Insulin-Like Growth Factor I; D003907:Dexamethasone; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D000077191:Wortmannin