title: MEK inhibitor effective against proliferation in breast cancer cell.
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.
authors.affiliation: Oncology Department of Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, No 600 Yishan Road Xuhui, Shanghai City, China, 200233.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Hu
authors.forename: Wei
authors.initials: W
authors.lastname: Meng
authors.forename: Ling
authors.initials: L
authors.lastname: Jiang
authors.forename: Xing
authors.initials: X
authors.lastname: Zhang
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Sha
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Lu
authors.forename: Yang
authors.initials: Y
authors.lastname: Yao
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001562:Benzimidazoles / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; C100318:Cullin 1; D044842:Cullin Proteins; C546703:MIRN203 microRNA, human; D035683:MicroRNAs; D047428:Protein Kinase Inhibitors; D020928:Mitogen-Activated Protein Kinases