title: Inhibition of Aurora-A suppresses epithelial-mesenchymal transition and invasion by downregulating MAPK in nasopharyngeal carcinoma cells.
abstract: Mitotic serine/threonine kinase Aurora-A (Aur-A) plays a critical role in regulating centrosome segregation and spindle assemble. Aur-A overexpression causes excessive centrosome duplication and abnormal spindle structure, leading to tumor malignant progression. Here, we investigated Aur-A expression in nasopharyngeal carcinoma (NPC) and the association between Aur-A and NPC invasiveness. We showed that overexpression of Aur-A in tumor tissues was correlated with cranial bone invasion and clinical stage in NPC patients. Suppression of Aur-A by either selective Aurora inhibitory VX-680 or small-interfering RNA caused G(2)/M arrest and apoptotic cell death in NPC CNE-2 cells. Significantly, inhibition of Aur-A suppressed CNE-2 cell invasion and restored membrane expression of epithelial markers, E-cadherin and beta-catenin, suggesting a reversed epithelial-mesenchymal transition process in cancer cells. In addition, we found that Aur-A-regulated epithelial-mesenchymal transition and invasion were mediated by mitogen-activated protein kinase (MAPK) phosphorylation. Moreover, suppression of MAP kinase by small-interfering RNA or its upstream MEK1/2-selective inhibitor U0126 abrogated cell invasion enhanced by Aur-A overexpression. On the other hand, forced overexpression of constitutively active form of MEK1/2, MEK2DD, in CNE-2 cancer cells rescued cell invasive ability suppressed by VX-680-imposed Aur-A inhibition. Our results indicated that Aur-A acted through a downstream MAP kinase pathway to promote epithelial-mesenchymal transition and invasiveness in nasopharyngeal tumorigenesis. Small chemical inhibitor VX-680 may offer as a promising molecular targeting agent in human NPC.
authors.affiliation: State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Sun Yat-sen University, 651 Dongfeng Road East, Guangzhou 510060, China.
authors.forename: Xiang-Bo
authors.initials: XB
authors.lastname: Wan
authors.forename: Zi-Jie
authors.initials: ZJ
authors.lastname: Long
authors.forename: Min
authors.initials: M
authors.lastname: Yan
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.forename: Liang-Ping
authors.initials: LP
authors.lastname: Xia
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.forename: Xue-Fei
authors.initials: XF
authors.lastname: Huang
authors.forename: Xian-Ren
authors.initials: XR
authors.lastname: Wang
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Zhu
authors.forename: Ming-Huang
authors.initials: MH
authors.lastname: Hong
authors.forename: Quentin
authors.initials: Q
authors.lastname: Liu
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D064127:Aurora Kinases; D002070:Butadienes / Q000494:pharmacology; D015820:Cadherins / Q000032:analysis; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004848:Epithelium / Q000473:pathology*; D006801:Humans; D020935:MAP Kinase Signaling System; D008648:Mesoderm / Q000473:pathology*; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009303:Nasopharyngeal Neoplasms / Q000201:enzymology / Q000209:etiology / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D051176:beta Catenin / Q000032:analysis; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
chemical_list: D064127:Aurora Kinases; D002070:Butadienes; D015820:Cadherins; D020928:Mitogen-Activated Protein Kinases; D009570:Nitriles; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D051176:beta Catenin; C113580:U 0126; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines