title: Selumetinib suppresses cell proliferation, migration and trigger apoptosis, G1 arrest in triple-negative breast cancer cells.
abstract: Triple-negative breast cancer (TNBC) has aggressive progression with poor prognosis and ineffective treatments. Selumetinib is an allosteric, ATP-noncompetitive inhibitor of MEK1/2, which has benn known as effective antineoplastic drugs for several malignant tumors. We hypothesized that Selumetinib might be potential drug for TNBC and explore the mechanism.
  
  
  
  After treated with Selumetinib, the viability and mobility of HCC1937 and MDA-MB-231 were detected by MTT, tunnel, wound-healing assay, transwell assay and FCM methods. MiR array was used to analysis the change of miRs. We predicted and verified CUL1 is the target of miR-302a using Luciferase reporter assay. We also silenced the CUL1 by siRNA, to clarify whether CUL1 take part in the cell proliferation, migration and regulated its substrate TIMP1 and TRAF2. Moreover, after transfection, the antagomir of miR-302a and CUL1 over-expressed plasmid into HCC1937 and MDA-MB-231 cell accompanied with the Selumetinib treatment, we detected the proliferation and migration again.
  
  
  
  Selumetinib reduce the proliferation, migration, triggered apoptosis and G1 arrest in TNBC cell lines. In this process, the miR-302a was up-regulated and inhibited the CUL1 expression. The later negatively regulated the TIMP1 and TRAF2. As soon as we knockdown miR-302a and over-expression CUL1 in TNBC cells, the cytotoxicity of Selumetinib was reversed.
  
  
  
  MiR-302a targeted regulated the CUL1 expression and mediated the Selumetinib-induced cytotoxicity of triple-negative breast cancer.
authors: Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
authors: Yan
authors: 0000-0002-5547-2668
authors: Y
authors: Zhou
authors: Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
authors: Shuchen
authors: S
authors: Lin
authors: Biophysics Department of Oregan State University, ALS-2139, Corvallis, OR, 97330, USA.
authors: Kuo-Fu
authors: KF
authors: Tseng
authors: Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
authors: Kun
authors: K
authors: Han
authors: Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
authors: Yaling
authors: Y
authors: Wang
authors: Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
authors: Zhi-Hua
authors: ZH
authors: Gan
authors: Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China. mindaliu@csco.org.cn.|Biophysics Department of Oregan State University, ALS-2139, Corvallis, OR, 97330, USA. mindaliu@csco.org.cn.
authors: Da-Liu
authors: DL
authors: Min
authors: Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China. xuri1104@163.com.
authors: Hai-Yan
authors: HY
authors: Hu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001562:Benzimidazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D016000:Cluster Analysis; D044842:Cullin Proteins / Q000235:genetics; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D035683:MicroRNAs / Q000235:genetics; D034622:RNA Interference; D059467:Transcriptome; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism
chemical_list: C517975:AZD 6244; D000970:Antineoplastic Agents; D001562:Benzimidazoles; C100318:Cullin 1; D044842:Cullin Proteins; C532169:MIRN302A microRNA, human; D035683:MicroRNAs
keywords: CUL1; Selumetinib; Triple-negative breast cancer; miR-302a