Aurora-A down-regulates IkappaB[alpha] via Akt activation and interacts with insulin-like growth factor-1 induced phosphatidylinositol 3-kinase pathway for cancer cell survival

• Published in: Molecular cancer 2009-11, Vol.8, p.95
• Main Authors: Yao, Jin-e, Yan, Min, Guan, Zhong, Pan, Chao-bin, Xia, Liang-ping, Li, Chuan-xing, Wang, Li-hui, Long, Zi-jie, Zhao, Yan, Li, Ming-wei, Zheng, Fei-meng, Xu, Jie, Lin, Dong-jun, Liu, Quentin
• Format: Article
• Language: English
• Subjects: Cancer; Care and treatment; Cellular signal transduction; Development and progression; Enzymes; Genes; Genetic aspects; Insulin-like growth factor 1; Insulin-like growth factors; Kinases; Physiological aspects; Proteins; Transcription factors
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/1476-4598-8-95

Background The mitotic Aurora-A kinase exerts crucial functions in maintaining mitotic fidelity. As a bona fide oncoprotein, Aurora-A aberrant overexpression leads to oncogenic transformation. Yet, the mechanisms by which Aurora-A enhances cancer cell survival remain to be elucidated. Results Here, we found that Aurora-A overexpression was closely correlated with clinic stage and lymph node metastasis in tongue carcinoma. Aurora-A inhibitory VX-680 suppressed proliferation, induced apoptosis and markedly reduced migration in cancer cells. We further showed that insulin-like growth factor-1, a PI3K physiological activator, reversed VX-680-decreased cell survival and motility. Conversely, wortmannin, a PI3K inhibitor, combined with VX-680 showed a synergistic effect on inducing apoptosis and suppressing migration. In addition, Aurora-A inhibition suppressed Akt activation, and VX-680-induced apoptosis was attenuated by Myr-Akt overexpression, revealing a cross-talk between Aurora-A and PI3K pathway interacting at Akt activation. Significantly, we showed that suppression of Aurora-A decreased phosphorylated Akt and was associated with increased IkappaB[alpha] expression. By contrast, Aurora-A overexpression upregulated Akt activity and downregulated IkappaB[alpha], these changes were accompanied by nuclear translocation of nuclear factor-[kappa]B and increased expression of its target gene Bcl-xL. Lastly, Aurora-A overexpression induced IkappaB[alpha] reduction was abrogated by suppression of Akt either chemically or genetically. Conclusion Taken together, our data established that Aurora-A, via activating Akt, stimulated nuclear factor-[kappa]B signaling pathway to promote cancer cell survival, and promised a novel combined chemotherapy targeting both Aurora-A and PI3K in cancer treatment.