Requirement for the PI3K Akt pathway in MEK1-mediated growth and prevention of apoptosis: identification of an Achilles heel in leukemia

• Published in: Leukemia Vol. 17; no. 6; pp. 1058 - 1067
• Main Authors: BLALOCK, W. L, NAVOLANIC, P. M, MCCUBREY, J. A, STEELMAN, L. S, SHELTON, J. G, MOYE, P. W, LEE, J. T, FRANKLIN, R. A, MIRZA, A, MCMAHON, M, WHITEN, M. K
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 01.06.2003; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; 17β-Estradiol; AKT protein; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Blotting, Western; Cancer; Cell Division - drug effects; Cell growth; Cell proliferation; Cell surface; Cytokines; Deprivation; Enzyme Inhibitors - pharmacology; Estrogen receptors; Estrogens; Extracellular signal-regulated kinase; Granulocytes; Hematologic and hematopoietic diseases; Immunology; Inhibitors; Interleukin 3; Interleukin-3 - pharmacology; Kinases; Leukemia; Leukemia, Myeloid - drug therapy; Leukemia, Myeloid - metabolism; Leukemia, Myeloid - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Ligands; MAP Kinase Kinase 1; Medical sciences; MEK inhibitors; Mice; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase Kinases - genetics; Mitogen-Activated Protein Kinase Kinases - pharmacology; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Prevention; Protein kinase; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - pharmacology; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-raf - metabolism; Raf protein; Receptors; Receptors, Estrogen - metabolism; Retroviridae; Ribosomal protein S6 kinase; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; Sex hormones; Signal transduction; Signal Transduction - drug effects; Signal Transduction - physiology; Tumor Cells, Cultured - drug effects; Tumor Cells, Cultured - metabolism; United States > US; Human; Cell proliferation; Enzyme; Transferases; Leukemia; Mitogen-activated protein kinase; oncogenes; Malignant hemopathy; Akt; 1-Phosphatidylinositol 3-kinase; Signal transduction; PI3K; Cell death; Protein kinase; MEK1; cytokines; P70S6K; Apoptosis
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/sj.leu.2402925

The Raf/MEK/ERK kinase cascade plays a critical role in transducing growth signals from activated cell surface receptors. Using DeltaMEK1:ER, a conditionally active form of MEK1 which responds to either beta-estradiol or the estrogen receptor antagonist 4 hydroxy-tamoxifen (4HT), we previously documented the ability of this dual specificity protein kinase to abrogate the cytokine-dependency of human (TF-1) and murine (FDC-P1 and FL5.12) hematopoietic cells lines. Here we demonstrate the ability of DeltaMEK1:ER to activate the phosphatidylinositol 3-kinase (PI3K)/Akt/p70 ribosomal S6 kinase (p70(S6K)) pathway and the importance of this pathway in MEK1-mediated prevention of apoptosis. MEK1-responsive cells can be maintained long term in the presence of beta-estradiol, 4HT or IL-3. Removal of hormone led to the rapid cessation of cell proliferation and the induction of apoptosis in a manner similar to cytokine deprivation of the parental cells. Stimulation of DeltaMEK1:ER by 4HT resulted in ERK, PI3K, Akt and p70(S6K) activation. Treatment with PI3K, Akt and p70(S6K) inhibitors prevented MEK-responsive growth. Furthermore, the apoptotic effects of PI3K/Akt/p70(S6K) inhibitors could be enhanced by cotreatment with MEK inhibitors. Use of a PI3K inhibitor and a constitutively active form of Akt, [DeltaAkt(Myr(+))], indicated that activation of PI3K was necessary for MEK1-responsive growth and survival as activation of Akt alone was unable to compensate for the loss of PI3K activity. Cells transduced by MEK or MEK+Akt displayed different sensitivities to signal transduction inhibitors, which targeted these pathways. These results indicate a requirement for the activation of the PI3K pathway during MEK-mediated transformation of certain hematopoietic cells. These experiments provide important clues as to why the identification of mutant signaling pathways may be the Achilles heel of leukemic cell growth. Leukemia treatment targeting multiple signal transduction pathways may be more efficacious than therapy aimed at inhibiting a single pathway.