Artikel
Impact of p53 on differential immunogenic stress responses of AZD1152-HQPA-treated polyploid glioma cells
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Veröffentlicht: | 8. Juni 2016 |
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Gliederung
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Objective: The “Chromosomal Passenger Complex” (CPC) is one of the key regulators of cell division involved in the coordination of chromosomal and cytoskeletal events. The enzymatically active member of the complex is the Aurora B kinase which critically safeguards bi-orientated chromosome segregation and cytokinesis. Constant interference with the chromosomal passenger complex by using selective inhibitors for Aurora B kinase causes polyploidy and finally results in a p53-independent and non-apoptotic cell death (i.e. mitotic catastrophe). However, since suboptimal concentrations or insufficient treatment times using Aurora B inhibitors promotes the outgrowth of progenies with increased aneuploidy we sought to investigate whether a potential p53-dependent stress response following treatment with the selective Aurora B inhibitor AZD1152-HQPA (Barasertib) induces an immune response of NK cells.
Method: U87-MGwt, U87-MGshp53 and primary HT7606 glioma cells were incubated with the selective Aurora B inhibitor AZD1152-HQPA (Barasertib). Cells were analyzed for induction of apoptosis and cell death using flow cytometry and immunoblotting. Expression levels of death receptors and MICA/B stress proteins were assessed by FACS-analysis. The specific cytotoxicity of allogenic human NK cells against AZD1152-HQPA-treated glioma cells was assessed by chrome release assay.
Results: Treatment with AZD1152-HQPA induced an 4-fold increase of MICA/B stress proteins in p53-deficient cells and an up to thirty times greater expression of death receptor FAS/CD95 in cells containing p53 (n=3; p<0.05). TRAILR2/DR5 expression levels increased 5-fold after treatment in U87-MG cells containing p53 wild type as well as in U87-MGshp53 cells (n=3; p<0.05). Upregulation of death receptors as well as MICA/B stress proteins rendered AZD1152-HQPA-treated glioma cells more susceptible for NK cell mediated lysis.
Conclusions: We conclude that increase in death receptors and MICA/B following Aurora B inhibition might induce anti-tumoral immune responses. The immunogenic effects caused by Aurora B inhibition could be exploited therapeutically by applying for instance NKG2D-Fc or an immune checkpoint blockade, respectively, which should constrain glioma growth.