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Carcinogenesis Advance Access published online on July 30, 2008
Carcinogenesis, doi:10.1093/carcin/bgn176
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Inhibition of Aurora-A suppresses epithelial-mesenchymal transition and invasion by down-regulating MAPK in nasopharyngeal carcinoma cells

Xiang-bo Wan1,2,{dagger}, Zi-jie Long1,{dagger}, Min Yan1,{dagger}, Jie Xu1, Liang-ping Xia1, Li Liu1, Yan zhao1, Xue-fei Huang1, Xian-ren Wang1, Xiao-feng Zhu1, Ming-huang Hong2 and Quentin Liu1,*

1 State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Cancer Center
2 Department of Nasopharyngeal Carcinoma, Cancer Center, Sun Yat-sen University, Guangzhou, China

* To whom correspondence should be addressed at: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University; 651 Dongfeng Road East, Guangzhou 510060, China; Tel: +86-20-87343148; Fax: +86-20-87343171; E-mail: liuqlab{at}yahoo.com.

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 (siRNA) caused G2/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 β-catenin, suggesting a reversed EMT process in cancer cells. In addition, we found that Aur-A-regulated EMT and invasion were mediated by MAPK phosphorylation. Moreover, suppression of MAPK by siRNA 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 MAPK pathway to promote EMT and invasiveness in nasopharyngeal tumorigenesis. Small chemical inhibitor VX-680 may offer as a promising molecular targeting agent in human NPC.

Key Words: Aur-A • invasion • epithelial-mesenchymal transition • MAPK signaling • NPC

{dagger} These authors contributed equally to this work.

Received April 13, 2008; revised July 11, 2008; accepted July 25, 2008.


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