title: 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.affiliation: Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China; Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin 300052, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Department of Head & Neck, Tianjin Cancer Institute and Hospital, Tianjin 300060, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Juan-Juan
authors.initials: JJ
authors.lastname: Yang
authors.affiliation: Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Obstetrics and Gynecology, Tianjin Medical University General Hospital, Tianjin 300052, China.
authors.forename: Xiao-hui
authors.initials: XH
authors.lastname: Zhao
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin 300052, China.
authors.forename: Qi-xue
authors.initials: QX
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin 300052, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Han
authors.affiliation: Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Song
authors.affiliation: Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Zhi-yan
authors.initials: ZY
authors.lastname: Zhu
authors.affiliation: Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Wei-ping
authors.initials: WP
authors.lastname: Tian
authors.affiliation: Department of Head & Neck, Tianjin Cancer Institute and Hospital, Tianjin 300060, China.
authors.forename: Lun
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China. Electronic address: mei_10668@163.com.
authors.forename: Mei
authors.initials: M
authors.lastname: Mei
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin 300052, China. Electronic address: kang97061@gmail.com.
authors.forename: Chun-sheng
authors.initials: CS
authors.lastname: Kang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D063646:Carcinogenesis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D051360:Cyclin-Dependent Kinase 5 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays
chemical_list: C584580:AC1MMYR2 compound; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D011743:Pyrimidines; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; D017239:Paclitaxel
keywords: AC1MMYR2; CDK5; CDK5RAP1; Metastasis; Taxol