title: ZM 447439 inhibition of aurora kinase induces Hep2 cancer cell apoptosis in three-dimensional culture.
abstract: Mitotic Aurora kinases are essential for accurate chromosome segregation during cell division. Forced overexpression of Aurora kinase results in centrosome amplification and multipolar spindles, causing aneuploidy, a hallmark of cancer. ZM447439 (ZM), an Aurora selective ATP-competitive inhibitor, interferes with the spindle integrity checkpoint and chromosome segregation. Here, we showed that inhibition of Aurora kinase by ZM reduced histone H3 phosphorylation at Ser10 in Hep2 carcinoma cells. Multipolar spindles were induced in these ZM-treated G(2)/M-arrested cells with accumulation of 4N/8N DNA, similar to cells with genetically suppressed Aurora-B. Cells subsequently underwent apoptosis, as assessed by cleavage of critical apoptotic associated protein PARP. Hep2 cells formed a tumor-like cell mass in 3-dimensional matrix culture; inhibition of Aurora kinase by ZM either destructed the preformed cell mass or prevented its formation, by inducing apoptotic cell death as stained for cleaved caspase-3. Lastly, ZM inhibition of Aurora kinase was potently in association with decrease of Akt phosphorylation at Ser473 and its substrates GSK3alpha/beta phosphorylation at Ser21 and Ser9. Together, we demonstrated that Aurora kinase served as a potential molecular target of ZM for more selective therapeutic cancer treatment.
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Zi-Jie
authors.initials: ZJ
authors.lastname: Long
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.forename: Min
authors.initials: M
authors.lastname: Yan
authors.forename: Jian-Gang
authors.initials: JG
authors.lastname: Zhang
authors.forename: Zhong
authors.initials: Z
authors.lastname: Guan
authors.forename: Da-Zhi
authors.initials: DZ
authors.lastname: Xu
authors.forename: Xian-Ren
authors.initials: XR
authors.lastname: Wang
authors.forename: Jine
authors.initials: J
authors.lastname: Yao
authors.forename: Fei-Meng
authors.initials: FM
authors.lastname: Zheng
authors.forename: Guo-Liang
authors.initials: GL
authors.lastname: Chu
authors.forename: Jun-Xia
authors.initials: JX
authors.lastname: Cao
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Zeng
authors.forename: Quentin
authors.initials: Q
authors.lastname: Liu
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001549:Benzamides / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D020090:Chromosome Segregation / Q000187:drug effects*; D024161:Collagen Type XI / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006657:Histones / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: C474722:4-(4-(N-benzoylamino)anilino)-6-methoxy-7-(3-(1-morpholino)propoxy)quinazoline; D001549:Benzamides; C499319:COL11A2 protein, human; D024161:Collagen Type XI; D006657:Histones; D011799:Quinazolines; D034741:RNA, Small Interfering; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases