title: Vandetanib-induced inhibition of neuroblastoma cell migration and invasion is associated with downregulation of the SDF-1/CXCR4 axis and matrix metalloproteinase 14.
abstract: Rearranged during transfection (RET) is widely expressed in neuroblastoma (NB) and partly contributes to high metastatic potential and survival of NB. The aim of the present study was to investigate whether vandetanib (a RET inhibitor) inhibits proliferation, migration and invasion of NB cells in vitro. The effects of vandetanib on the proliferation, apoptosis and cell cycle and on RET phosphorylation of SK-N-SH and SH-SY5Y cells were evaluated in vitro. The migration and invasion potential of vandetanib-treated NB cells were analyzed using Transwell cell migration and invasion assays, respectively. qPCR, western blotting and immunofluorescence were used to detect mRNA and protein levels in NB cells treated with vandetanib. Our data demonstrated that vandetanib inhibits the proliferation of SK-N-SH and SH-SY5Y cells and that this inhibition is mediated by the induction of G1 phase cell cycle arrest at lower concentrations and by apoptosis at higher concentrations. In the presence of vandetanib, the migration and invasion of two NB cell lines were markedly decreased compared with the control group (p<0.01). In addition, our data showed that the levels of C-X-C chemokine receptor type 4 (CXCR4) and matrix metalloproteinase 14 (MMP14) mRNA expression in NB cell lines treated with vandetanib were significantly lower than those in the cells that were treated with vehicle (p<0.01) and similar results were obtained for protein levels as determined by western blotting and immunofluorescence analysis. Vandetanib may inhibit the proliferation, migration and invasion of NB cells in vitro. The potential mechanisms for the inhibition of NB migration and invasion by vandetanib may partly be attributed to the ability of vandetanib to suppress the expression of CXCR4 and MMP14 in human NB cells.
authors.affiliation: Ministry of Education Key Laboratory of Child Development and Disorders, Yuzhong, Chongqing 400014, P.R. China.
authors.forename: Xionghui
authors.initials: X
authors.lastname: Ding
authors.affiliation: Department of Neonatal Gastrointestinal Surgery, Children's Hospital of Chongqing Medical University, Yuzhong, Chongqing 400014, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Xiang
authors.affiliation: Ministry of Education Key Laboratory of Child Development and Disorders, Yuzhong, Chongqing 400014, P.R. China.
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.affiliation: Ministry of Education Key Laboratory of Child Development and Disorders, Yuzhong, Chongqing 400014, P.R. China.
authors.forename: Zhanbo
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Pediatrics in Chongqing, Children's Hospital of Chongqing Medical University, Yuzhong, Chongqing 400014, P.R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Jin
authors.affiliation: Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Children's Hospital of Chongqing Medical University, Yuzhong, Chongqing 400014, P.R. China.
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Ministry of Education Key Laboratory of Child Development and Disorders, Yuzhong, Chongqing 400014, P.R. China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Duan
authors.affiliation: Ministry of Education Key Laboratory of Child Development and Disorders, Yuzhong, Chongqing 400014, P.R. China.
authors.forename: Shiqi
authors.initials: S
authors.lastname: Wang
authors.affiliation: Ministry of Education Key Laboratory of Child Development and Disorders, Yuzhong, Chongqing 400014, P.R. China.
authors.forename: Xianqing
authors.initials: X
authors.lastname: Jin
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D004354:Drug Screening Assays, Antitumor; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009447:Neuroblastoma; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D010880:Piperidines; D011799:Quinazolines; D019718:Receptors, CXCR4; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14; C452423:vandetanib