AC1MMYR2 impairs high dose paclitaxel-induced tumor metastasis by targeting miR-21/CDK5 axis
AC1MMYR2 impairs high dose paclitaxel-induced tumor metastasis by targeting miR-21/CDK5 axis
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AC1MMYR2通过靶向miR-21/CDK5轴损害高剂量紫杉醇诱导的肿瘤转移
DOI：
10.1016/j.canlet.2015.03.038
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发表时间：
2015-07-01
期刊：
影响因子：
9.7
通讯作者：
Kang, Chun-sheng
中科院分区：
文献类型：
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作者：
Ren, Yu;Zhou, Xuan;Kang, Chun-sheng
紫杉醇（紫杉醇）是一种广泛用于许多实体瘤的化学药物，而持续的紫杉醇治疗被发现会刺激肿瘤扩散。我们先前发现，一种名为AC 1 MMYR 2的miR-21小分子抑制剂具有损害肿瘤发生和转移的潜力。本研究的目的是调查是否可以探索将AC 1 MMYR 2与紫杉醇组合作为限制肿瘤转移的手段。我们发现miR-21/CDK 5轴的异常激活与乳腺癌淋巴结转移有关，并与高剂量紫杉醇诱导的乳腺癌细胞株MDA-MB-231和胶质母细胞瘤细胞株U87 VIII的侵袭和上皮间质转化（EMT）有关。AC 1 MMYR 2通过功能性靶向CDK 5 RAP 1、CDK 5激活剂p39和靶向p-FAK（ser 732）来减弱CDK 5活性。一系列体外实验表明，AC 1 MMYR 2联合紫杉醇处理MDA-MB-231和U87 VIII细胞可抑制肿瘤的迁移和侵袭能力。更重要的是，联合治疗损害了高剂量紫杉醇诱导的侵袭性伪足和EMT标志物，包括β-连环蛋白、E-钙粘蛋白和波形蛋白。引人注目的是，在AC 1 MMYR 2加紫杉醇治疗中观察到小鼠肺转移的显著减少。综上所述，我们的工作表明，AC 1 MMYR 2似乎是一个有前途的策略，在对抗紫杉醇诱导的肿瘤转移，通过靶向miR-21/CDK 5轴，这突出了潜在的发展，更好地临床应用紫杉醇的治疗模式。(C)2015爱思唯尔爱尔兰有限公司版权所有。
Paclitaxel (taxol) is a widely used chemo-drug for many solid tumors, while continual taxol treatment is revealed to stimulate tumor dissemination. We previously found that a small molecule inhibitor of miR-21, termed AC1MMYR2, had the potential to impair tumorigenesis and metastasis. The aim of this study was to investigate whether combining AC1MMYR2 with taxol could be explored as a means to limit tumor metastasis. Here we showed that abnormal activation of miR-21/CDK5 axis was associated with breast cancer lymph node metastasis, which was also contribute to high dose taxol-induced invasion and epithelial mesenchymal transition (EMT) in both breast cancer cell line MDA-MB-231 and glioblastoma cell line U87 VIII. AC1MMYR2 attenuated CDK5 activity by functional targeting CDK5RAP1, CDK5 activator p39 and target p-FAK(ser732). A series of in vitro assays indicated that treatment of AC1MMYR2 combined with taxol suppressed tumor migration and invasion ability in both MDA-MB-231 and U87VIII cell. More importantly, combination therapy impaired high-dose taxol induced invadopodia, and EMT markers including beta-catenin, E-cadherin and vimentin. Strikingly, a significant reduction of lung metastasis in mice was observed in the AC1MMYR2 plus taxol treatment. Taken together, our work demonstrated that AC1MMYR2 appeared to be a promising strategy in combating taxol induced cancer metastasis by targeting miR-21/CDK5 axis, which highlighted the potential for development of therapeutic modalities for better clinic taxol application. (C) 2015 Elsevier Ireland Ltd. All rights reserved.