Selumetinib suppresses cell proliferation, migration and trigger apoptosis, G1 arrest in triple-negative breast cancer cells.
Selumetinib suppresses cell proliferation, migration and trigger apoptosis, G1 arrest in triple-negative breast cancer cells.
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Selumetinib 抑制三阴性乳腺癌细胞中的细胞增殖、迁移并引发细胞凋亡、G1 期停滞。
DOI：
10.1186/s12885-016-2773-4
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发表时间：
2016-10-21
期刊：
影响因子：
3.8
通讯作者：
Hu HY
中科院分区：
文献类型：
--
作者：
Zhou Y;Lin S;Tseng KF;Han K;Wang Y;Gan ZH;Min DL;Hu HY
三阴性乳腺癌（TNBC）具有侵袭性进展，预后不良且治疗无效。Selumetinib是一种别构的、ATP非竞争性的MEK 1/2抑制剂，是治疗多种恶性肿瘤的有效药物。我们推测Selumetinib可能是治疗TNBC的潜在药物，并探讨其作用机制。用MTT法、隧道法、创伤愈合实验、transwell实验和流式细胞术检测Selumetinib作用后HCC 1937和MDA-MB-231细胞的存活率和迁移率。MiR阵列分析miR的变化。我们利用荧光素酶报告基因实验预测并验证了CUL 1是miR-302 a的靶点。我们还利用siRNA沉默了CUL 1基因，以阐明CUL 1是否参与细胞增殖、迁移以及调控其底物TIMP 1和TRAF 2。将miR-302 a和CUL 1过表达质粒转染入HCC 1937和MDA-MB-231细胞后，伴随Selumetinib处理，再次检测细胞增殖和迁移情况。Selumetinib可降低TNBC细胞系的增殖、迁移、触发凋亡和G1期阻滞。在此过程中，miR-302 a上调并抑制了CUL 1的表达。后者负性调节TIMP 1和TRAF 2。一旦我们在TNBC细胞中敲低miR-302 a和过表达CUL 1，司美替尼的细胞毒性就被逆转。MiR-302 a靶向调节CUL 1表达并介导Selumetinib诱导的三阴性乳腺癌细胞毒性。
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.
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DOI：
10.1056/nejmoa1209288
发表时间：
2013-02-14
期刊：
The New England journal of medicine
影响因子：
--
作者：
Ho AL;Grewal RK;Leboeuf R;Sherman EJ;Pfister DG;Deandreis D;Pentlow KS;Zanzonico PB;Haque S;Gavane S;Ghossein RA;Ricarte-Filho JC;Domínguez JM;Shen R;Tuttle RM;Larson SM;Fagin JA
通讯作者：
Fagin JA
影响因子：
1.3
作者：
Griffiths, Carrie L;Olin, Jacqueline L
通讯作者：
Olin, Jacqueline L
影响因子：
5.2
作者：
Chen, Guangdi;Li, Gang
通讯作者：
Li, Gang
影响因子：
5.2
作者：
Hu, Shijun;Wilson, Kitchener D.;Ghosh, Zhumur;Han, Leng;Wang, Yongming;Lan, Feng;Ransohoff, Katherine J.;Burridge, Paul;Wu, Joseph C.
通讯作者：
Wu, Joseph C.
Cullin1过度表达与胃癌患者不良预后相关
影响因子：
3.3
作者：
Bai, Jin;Zhou, Yan;Li, Gang
通讯作者：
Li, Gang