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Carcinogenesis Advance Access originally published online on July 30, 2008
Carcinogenesis 2008 29(10):1930-1937; 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 downregulating 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
2 Department of Nasopharyngeal Carcinoma, Cancer Center, Sun Yat-sen University, 651 Dongfeng Road East, Guangzhou 510060, China

* To whom correspondence should be addressed. Tel: +86 20 87343148; Fax: +86 20 87343171; Email: 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 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 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.

Abbreviations: Aur-A, Aurora-A; DAPI, 4',6-diamidino-2-phenylindole; EMT, epithelial–mesenchymal transition; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; IKK, I{kappa}B kinase; MAPK, mitogen-activated protein kinase; NF-{kappa}B, nuclear factor-kappa B; NPC, nasopharyngeal carcinoma; siRNA, small-interfering RNA

{dagger} These authors contributed equally to this work.

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


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