Radiation promotes malignant progression of glioma cells through HIF-1alpha stabilization

Abstract

Given its contribution to malignant phenotypes of cancer, tumor hypoxia has been considered as a potential therapeutic problem. In the stressful microenvironment condition, hypoxia inducible factor 1 (HIF1) is well known to mediate the transcriptional adaptation of cells to hypoxia and acts as a central player for the process of hypoxia-driven malignant cancer progression. Here, we found that irradiation causes the HIF1 alpha protein to stabilize, even in normoxia condition through activation of p38 MAPK, thereby promoting angiogenesis in tumor microenvironment and infiltrative property of glioma cells. Notably, irradiation reduced hydroxylation of HIF1 alpha through destabilization of prolyl hydroxylases (PHD)-2. Moreover, radiation also decreased the half-life of protein von Hippel-Lindau (pVHL), which is a specific E3 ligase for HIF1 alpha. Of note, inhibition of p38 MAPK attenuated radiation-induced stabilization of HIF1 alpha through destabilization of PHD-2 and pVHL. In agreement with these results, targeting of either p38 MAPK, HIF1 alpha, pVHL or PHD-2 effectively mitigated the radiation-induced tube formation of human brain-derived micro-vessel endothelial cells (HB-MEC) and infiltration of glioma cells. Taken together, our findings suggest that targeting HIF1a in combination with ionizing radiation might increase the efficacy of radiotherapy for glioma treatment. (C) 2014 Elsevier Ireland Ltd. All rights reserved.