title: Inhibition of Aurora-A results in increased cell death in 3-dimensional culture microenvironment, reduced migration and is associated with enhanced radiosensitivity in human nasopharyngeal carcinoma.
abstract: Mitosis related Aurora-A kinase is amplified in a variety of carcinomas. Overexpression of Aurora-A contributes to tumorigenesis and disease progression, and has emerged as an attractive molecular target for the design of anticancer drugs. In this study, we investigated the function of Aurora-A selectively small molecule inhibitor VX-680 in nasopharyngeal carcinoma (NPC) CNE-2 cells. We found that VX-680 suppressed proliferation and induced apoptosis of 2Dimensional (2D) cultured NPC CNE-2 cells. Moreover, CNE-2 cells formed a tumor-like cell mass in 3Dimensional (3D) matrix culture microenvironment, and the tumor mass formation could be impaired when pretreated with VX-680 for indicated time. Similarly, when adding VX-680 to preformed 3D CNE-2 tumor mass, the tight spatial tumor mass experienced apparent apoptotic cell death and consequently dissociated into individual dead cells, as detected by cleaved Caspase-3 immunofluorescence assay. The migration assay showed that VX-680 decreased NPC CNE-2 cell migration ability in a dose-dependent manner. Our further study revealed that X-ray irradiation and VX-680 upregulated p53 expression level as well as arrested cell cycle in G(2)/M, sensitized NPC CNE-2 cells to radiation and effectively resulted in cell death. In summary, our data indicated that Aurora-A small molecule inhibitor VX-680, potently destructed tumor formation and induced apoptosis, reduced cell migration and enhanced radiosensitivity, offering a promising therapeutic agent for human NPC.
authors.affiliation: State Key Laboratory of Oncology in Southern China, Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Xiang-Bo
authors.initials: XB
authors.lastname: Wan
authors.forename: Xin-Juan
authors.initials: XJ
authors.lastname: Fan
authors.forename: Ming-Yuan
authors.initials: MY
authors.lastname: Chen
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.forename: Zi-Jie
authors.initials: ZJ
authors.lastname: Long
authors.forename: Yi-Jun
authors.initials: YJ
authors.lastname: Hua
authors.forename: Hong
authors.initials: H
authors.lastname: Ji
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Ming-Huang
authors.initials: MH
authors.lastname: Hong
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Zeng
authors.forename: Quentin
authors.initials: Q
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D064127:Aurora Kinases; D002277:Carcinoma / Q000201:enzymology / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016158:Genes, p53; D006801:Humans; D009303:Nasopharyngeal Neoplasms / Q000201:enzymology / Q000473:pathology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D011836:Radiation Tolerance / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology / Q000528:radiation effects; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
chemical_list: D000970:Antineoplastic Agents; D064127:Aurora Kinases; D009363:Neoplasm Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines