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 HIF1α 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 HIF1α 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 HIF1α. Of note, inhibition of p38 MAPK attenuated radiation-induced stabilization of HIF1α through destabilization of PHD-2 and pVHL. In agreement with these results, targeting of either p38 MAPK, HIF1α, 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 HIF1α in combination with ionizing radiation might increase the efficacy of radiotherapy for glioma treatment.

journal_name

Cancer Lett

journal_title

Cancer letters

authors

Kim YH,Yoo KC,Cui YH,Uddin N,Lim EJ,Kim MJ,Nam SY,Kim IG,Suh Y,Lee SJ

doi

10.1016/j.canlet.2014.07.048

subject

Has Abstract

pub_date

2014-11-01 00:00:00

pages

132-41

issue

1

eissn

0304-3835

issn

1872-7980

pii

S0304-3835(14)00427-3

journal_volume

354

pub_type

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