Selumetinib suppresses cell proliferation, migration and trigger apoptosis, G1 arrest in triple-negative breast cancer cells

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Background:
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.

Methods:
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.

Results:
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.

Conclusions:
MiR-302a targeted regulated the CUL1 expression and mediated the Selumetinib-induced cytotoxicity of triple-negative breast cancer.

Keywords:
Selumetinib, Triple-negative breast cancer, miR-302a, CUL1

Autoři: Yan Zhou† ¹; Shuchen Lin† ¹; Kuo-Fu Tseng ²; Kun Han ¹; Yaling Wang ¹; Zhi-Hua Gan ¹; Da-Liu Min ^1,2*; And Hai-Yan Hu ^1*
Působiště autorů: Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 00 33, China. ¹; Biophysics Department of Oregan State University, ALS-2139, Corvallis, OR 97330, USA. ²
Vyšlo v časopise: BMC Cancer 2016, 16:818
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1186/s12885-016-2773-4

© 2016 The Author(s).

Open access
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The electronic version of this article is the complete one and can be found online at: http://bmccancer.biomedcentral.com/articles/10.1186/s12885-016-2773-4

Souhrn

Conclusions:
MiR-302a targeted regulated the CUL1 expression and mediated the Selumetinib-induced cytotoxicity of triple-negative breast cancer.

Keywords:
Selumetinib, Triple-negative breast cancer, miR-302a, CUL1

Zdroje

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