title: Inhibition of Aurora-A kinase induces cell cycle arrest in epithelial ovarian cancer stem cells by affecting NFĸB pathway.
abstract: Recurrent ovarian cancer is resistant to conventional chemotherapy. A sub-population of ovarian cancer cells, the epithelial ovarian cancer stem cells (EOC stem cells) have stemness properties, constitutive NFκB activity, and represent the chemoresistant population. Currently, there is no effective treatment that targets these cells. Aurora-A kinase (Aurora-A) is associated with tumor initiation and progression and is overexpressed in numerous malignancies. The aim of this study is to determine the effect of Aurora-A inhibition in EOC stem cells. EOC stem cells were treated with the Aurora-A inhibitor, MK-5108. Cell growth was monitored by Incucyte real-time imaging system, cell viability was measured using the Celltiter 96 assay and cytokine levels were quantified using xMAP technology. The intracellular changes associated with MK-5108 treatment are: (1) polyploidy and cell cycle arrest; (2) inhibition of NFκB activity; (3) decreased cytokine production; and (4) nuclear accumulation of IκBα. Thus, inhibition of Aurora-A decreases cell proliferation in the EOC stem cells by inducing cell cycle arrest and affecting the NFκB pathway. As EOC stem cells represent a source of recurrence and chemoresistance, these results suggest that Aurora-A inhibition may effectively target the cancer stem cell population in ovarian cancer.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Reproductive Immunology Unit, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Ilana
authors.initials: I
authors.lastname: Chefetz
authors.forename: Jennie C
authors.initials: JC
authors.lastname: Holmberg
authors.forename: Ayesha B
authors.initials: AB
authors.lastname: Alvero
authors.forename: Irene
authors.initials: I
authors.lastname: Visintin
authors.forename: Gil
authors.initials: G
authors.lastname: Mor
mesh_terms: D064127:Aurora Kinases; D002453:Cell Cycle / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D005260:Female; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000473:pathology*; D011123:Polyploidy; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000502:physiology*; D013844:Thiazoles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C547876:4-(3-chloro-2-fluorophenoxy)-1-((6-(1,3-thiazol-2-ylamino)pyridin to 2-yl)methyl) cyclohexanecarboxylic acid; D003509:Cyclohexanecarboxylic Acids; D016328:NF-kappa B; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases