AC1MMYR2 impairs high dose paclitaxel-induced tumor metastasis by targeting miR-21/CDK5 axis.

Abstract

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 U87VIII. 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 β-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.

• Authors: Yu Ren, Xuan Zhou, Juan-Juan Yang, Xia Liu, Xiao-hui Zhao, Qi-xue Wang, Lei Han, Xin Song, Zhi-yan Zhu, Wei-ping Tian, Lun Zhang, Mei Mei, Chun-sheng Kang
• Journal: Cancer letters (Cancer Lett) Vol. 362 Issue 2 Pg. 174-82 (Jul 01 2015) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 25827073 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• AC1MMYR2 compound
• MIRN21 microRNA, human
• MicroRNAs
• Pyrimidines
• Cyclin-Dependent Kinase 5
• CDK5 protein, human
• Paclitaxel

Topics

• Animals
• Breast Neoplasms (drug therapy, genetics, metabolism, pathology)
• Carcinogenesis (drug effects)
• Cell Movement (drug effects)
• Cyclin-Dependent Kinase 5 (biosynthesis, genetics, metabolism)
• Dose-Response Relationship, Drug
• Drug Synergism
• Epithelial-Mesenchymal Transition (drug effects)
• Female
• Humans
• Lymphatic Metastasis
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• MicroRNAs (biosynthesis, genetics, metabolism)
• Molecular Targeted Therapy
• Neoplasm Metastasis
• Paclitaxel (administration & dosage, pharmacology)
• Pyrimidines (administration & dosage, pharmacology)
• Random Allocation
• Xenograft Model Antitumor Assays