Blockade of Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase and Murine Double Minute Synergistically Induces Apoptosis in Acute Myeloid Leukemia via BH3-Only Proteins Puma and Bim
| Autor: | Mien Chie Hung, Jared K. Burks, Michael Andreeff, Karen C. Dywer, Teresa McQueen, Marina Konopleva, Jer Yen Yang, Weiguo Zhang, Wendy D. Schober |
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| Rok vydání: | 2010 |
| Předmět: |
MAPK/ERK pathway
Cancer Research MAP Kinase Signaling System Apoptosis HL-60 Cells Biology Piperazines Article Proto-Oncogene Proteins hemic and lymphatic diseases Puma Humans Phosphorylation Extracellular Signal-Regulated MAP Kinases Protein kinase A neoplasms Bcl-2-Like Protein 11 Kinase Forkhead Box Protein O3 Imidazoles Membrane Proteins Myeloid leukemia Drug Synergism Forkhead Transcription Factors Proto-Oncogene Proteins c-mdm2 U937 Cells biology.organism_classification Myeloid Cell Leukemia Sequence 1 Protein Proto-Oncogene Proteins c-bcl-2 Oncology Leukemia Myeloid Mitogen-activated protein kinase Acute Disease biology.protein Cancer research Benzimidazoles biological phenomena cell phenomena and immunity Signal transduction Apoptosis Regulatory Proteins |
| Zdroj: | Cancer Research. 70:2424-2434 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Molecular aberrations of the Ras/Raf/mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK and/or Murine double minute (MDM2)/p53 signaling pathways have been reported in 80% and 50% of primary acute myeloid leukemia (AML) samples and confer poor outcome. In this study, antileukemic effects of combined MEK inhibition by AZD6244 and nongenotoxic p53 activation by MDM2 antagonist Nutlin-3a were investigated. Simultaneous blockade of MEK and MDM2 signaling by AZD6244 and Nutlin-3a triggered synergistic proapoptotic responses in AML cell lines [combination index (CI) = 0.06 ± 0.03 and 0.43 ± 0.03 in OCI/AML3 and MOLM13 cells, respectively] and in primary AML cells (CI = 0.52 ± 0.01). Mechanistically, the combination upregulated levels of BH3-only proteins Puma and Bim, in part via transcriptional upregulation of the FOXO3a transcription factor. Suppression of Puma and Bim by short interfering RNA rescued OCI/AML3 cells from AZD/Nutlin-induced apoptosis. These results strongly indicate the therapeutic potential of combined MEK/MDM2 blockade in AML and implicate Puma and Bim as major regulators of AML cell survival. Cancer Res; 70(6); 2424–34 |
| Databáze: | OpenAIRE |
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