title: Inhibition of Cdk2 activity decreases Aurora-A kinase centrosomal localization and prevents centrosome amplification in breast cancer cells.
abstract: Centrosome amplification plays a key role in the origin of chromosomal instability (CIN) during cancer development and progression. In this study, MCF-7 breast cancer cell lines harboring abrogated p53 function (vMCF-7DNp53) were employed to investigate the relationship between induction of genotoxic stress, activation of cyclin-A/Cdk2 and Aurora-A oncogenic signalings and development of centrosome amplification. Introduction of genotoxic stress in the vMCF-7DNp53 cell line by treatment with hydroxyurea (HU) induced centrosome amplification that was mechanistically linked to Aurora-A kinase activity. In cells carrying defective p53, the development of centrosome amplification also occurred following treatment with another DNA damaging agent, methotrexate. Importantly, we demonstrated that Aurora-A kinase-induced centrosome amplification was mediated by Cdk2 kinase since molecular inhibition of Cdk2 activity by SU9516 suppressed Aurora-A centrosomal localization and consequent centrosome amplification. In addition, we employed vMCF-7DRaf-1 cells that display high levels of endogenous cyclin-A and demonstrated that molecular targeting of Aurora-A by Alisertib reduces cyclin-A expression. Taken together, these findings demonstrate a novel positive feed-back loop between cyclin-A/Cdk2 and Aurora-A pathways in the development of centrosome amplification in breast cancer cells. They also provide the translational rationale for targeting 'druggable cell cycle regulators' as an innovative therapeutic strategy to inhibit centrosome amplification and CIN in breast tumors resistant to conventional chemotherapeutic drugs.
authors: Department of Biochemistry and Molecular Biology, Mayo Clinic, College of Medicine, Rochester, MN, USA.
authors: Alexey A
authors: AA
authors: Leontovich
authors: Jeffrey L
authors: JL
authors: Salisbury
authors: Massimiliano
authors: M
authors: Veroux
authors: Tiziano
authors: T
authors: Tallarita
authors: Daniel
authors: D
authors: Billadeau
authors: James
authors: J
authors: McCubrey
authors: James
authors: J
authors: Ingle
authors: Evanthia
authors: E
authors: Galanis
authors: Antonino B
authors: AB
authors: D'Assoro
mesh_terms: D064096:Aurora Kinase A / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D018385:Centrosome / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D043171:Chromosomal Instability / Q000187:drug effects; D019925:Cyclin A / Q000235:genetics / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology*; D061986:MCF-7 Cells; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D019925:Cyclin A; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D064096:Aurora Kinase A; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D006918:Hydroxyurea