Abstract
The targeted small-molecule drug AZD6244 is an allosteric, ATP-noncompetitive inhibitor of MEK1/2 that has shown activity against several malignant tumors. Here, we report that AZD6244 repressed cell growth and induced apoptosis and G1-phase arrest in the breast cancer cell lines MDA-MB-231 and HCC1937. Using microRNA (miRNA) arrays and quantitative RT-PCR, we found that miR-203 was up-regulated after AZD6244 treatment. In accordance with bioinformatics and luciferase activity analyses, CUL1 was found to be the direct target of miR-203. Furthermore, miR-203 inhibition and CUL1 overexpression reversed the cytotoxicity of AZD6244 on the MDA-MB-231 and HCC1937 cells. Collectively, our data indicate that miR-203 mediates the AZD6244-induced cytotoxicity of breast cancer cells and that the MEK/ERK/miR-203/CUL1 signaling pathway may participate in this process.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects*
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Benzimidazoles / pharmacology*
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Cell Line, Tumor
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Cell Proliferation / drug effects*
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Cell Survival / drug effects
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Cullin Proteins / genetics
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Cullin Proteins / metabolism
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Female
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G1 Phase Cell Cycle Checkpoints / drug effects*
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Gene Expression Regulation, Neoplastic
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Humans
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MicroRNAs / genetics
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Mitogen-Activated Protein Kinases / metabolism
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Oligonucleotide Array Sequence Analysis
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Protein Kinase Inhibitors / pharmacology
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / drug effects
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Up-Regulation
Substances
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AZD 6244
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Benzimidazoles
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Cullin 1
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Cullin Proteins
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MIRN203 microRNA, human
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MicroRNAs
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Protein Kinase Inhibitors
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Mitogen-Activated Protein Kinases