Inhibition of Aurora-A suppresses epithelial-mesenchymal transition and invasion by downregulating MAPK in nasopharyngeal carcinoma cells.
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.
Wan
Xiang-Bo
XB
State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Sun Yat-sen University, 651 Dongfeng Road East, Guangzhou 510060, China.
Long
Zi-Jie
ZJ
Yan
Min
M
Xu
Jie
J
Xia
Liang-Ping
LP
Liu
Li
L
Zhao
Yan
Y
Huang
Xue-Fei
XF
Wang
Xian-Ren
XR
Zhu
Xiao-Feng
XF
Hong
Ming-Huang
MH
Liu
Quentin
Q
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
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