title: Aurora-A down-regulates IkappaBalpha via Akt activation and interacts with insulin-like growth factor-1 induced phosphatidylinositol 3-kinase pathway for cancer cell survival.
abstract: 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 IkappaBalpha expression. By contrast, Aurora-A overexpression upregulated Akt activity and downregulated IkappaBalpha, these changes were accompanied by nuclear translocation of nuclear factor-kappaB and increased expression of its target gene Bcl-xL. Lastly, Aurora-A overexpression induced IkappaBalpha reduction was abrogated by suppression of Akt either chemically or genetically.
  
  
  CONCLUSIONS
  Taken together, our data established that Aurora-A, via activating Akt, stimulated nuclear factor-kappaB signaling pathway to promote cancer cell survival, and promised a novel combined chemotherapy targeting both Aurora-A and PI3K in cancer treatment.
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, 651 Dongfeng Road East, Guangzhou, PR China.
authors.forename: Jin-E
authors.initials: JE
authors.lastname: Yao
authors.forename: Min
authors.initials: M
authors.lastname: Yan
authors.forename: Zhong
authors.initials: Z
authors.lastname: Guan
authors.forename: Chao-Bin
authors.initials: CB
authors.lastname: Pan
authors.forename: Liang-Ping
authors.initials: LP
authors.lastname: Xia
authors.forename: Chuan-Xing
authors.initials: CX
authors.lastname: Li
authors.forename: Li-Hui
authors.initials: LH
authors.lastname: Wang
authors.forename: Zi-Jie
authors.initials: ZJ
authors.lastname: Long
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.forename: Ming-Wei
authors.initials: MW
authors.lastname: Li
authors.forename: Fei-Meng
authors.initials: FM
authors.lastname: Zheng
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.forename: Dong-Jun
authors.initials: DJ
authors.lastname: Lin
authors.forename: Quentin
authors.initials: Q
authors.lastname: Liu
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D064127:Aurora Kinases; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008207:Lymphatic Metastasis / Q000473:pathology; D000072000:NF-KappaB Inhibitor alpha; D009367:Neoplasm Staging; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014062:Tongue Neoplasms / Q000201:enzymology / Q000473:pathology*; D051996:Transcription Factor RelA / Q000378:metabolism; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
chemical_list: D064127:Aurora Kinases; D020672:I-kappa B Proteins; D007334:Insulin-Like Growth Factor I; D000072000:NF-KappaB Inhibitor alpha; D019869:Phosphatidylinositol 3-Kinases; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; D021122:Protein Subunits; D051057:Proto-Oncogene Proteins c-akt; D051996:Transcription Factor RelA; C000606204:NFKBIA protein, human; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines