Πέμπτη 7 Σεπτεμβρίου 2017

Recognition by Natural Killer cells of N6-isopentenyladenosine-treated human glioma cell lines

Abstract

Cancer cell stress induced by cytotoxic agents promote antitumor immune response. Here we observed that N6-isopentenyladenosine (iPA), an isoprenoid modified adenosine with a well established anticancer activity, was able to induce a significant upregulation of cell surface expression of NKG2D ligands on glioma cells in vitro and xenografted in vivo. Specifically suboptimal doses of iPA (0.1 and 1µM) control the selective upregulation of ULBP2 on p53wt-expressing U343MG and that of MICA/B on p53mut-expressing U251MG cells. This event made the glioblastoma cells a potent target for natural killer (NK) cell mediated recognition through a NKG2D restricted mechanism. p53 siRNA mediated knock-down and pharmacological inhibition (pifithrin-α), profoundly prevented the iPA action in restoring the immunogenicity of U343MG cells through a mechanism that is dependent upon p53 status of malignancy. Furthermore, accordingly to the preferential recognition of senescent cells by NK cells, we found that iPA treatment was critical for glioma cells entry in premature senescence through the induction of S and G2/M phase arrest.

Collectively, our results indicate that behind the well established cytotoxic and anti-angiogenic effects, iPA can also display an immune-mediated antitumor activity. The indirect engagement of the innate immune system and its additional activity in primary derived patient's glioma cell model (GBM17 and GBM37), fully increase its translational relevance and led to the exploitation of the isoprenoid pathway for a valid therapeutic intervention in anti-glioma research. This article is protected by copyright. All rights reserved.



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