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.
Bibliographical noteFunding Information:
two κB sites before a FOS essential promoter (a gift from Dr. S. This study was supported in part by Merck and grants from Ghosh, Yale University). Cells were stably transfected and lucif-NCI/NIH RO1CA127913, RO1CA118678, The Janet Burros erase activity measured as previously described in reference 10. Memorial Foundation, The Sands Family Foundation, The Cytokine profiling. Levels of cytokines and chemokines Brozman Foundation and the Discovery To Cure Research were measured from cell-free supernatants using the Bioplex Program. I.C. is Life Science Research Foundation Postdoctoral Pro Cytokine Assay (Biorad, Hercules, CA). Data were acquired Fellow.
- Aurora-A kinase
- Cell cycle arrest
- Nuclear factor kappaB
- Ovarian cancer stem cells