Radiation promotes malignant progression of glioma cells through HIF-1alpha stabilization.
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.
['Kim|Young-Heon|YH|', 'Yoo|Ki-Chun|KC|', 'Cui|Yan-Hong|YH|', 'Uddin|Nizam|N|', 'Lim|Eun-Jung|EJ|', 'Kim|Min-Jung|MJ|', 'Nam|Seon-Young|SY|', 'Kim|In-Gyu|IG|', 'Suh|Yongjoon|Y|', 'Lee|Su-Jae|SJ|']
D001932:Brain Neoplasms D045744:Cell Line, Tumor D002465:Cell Movement D003094:Collagen D018450:Disease Progression D019583:Dose Fractionation, Radiation D004338:Drug Combinations D005910:Glioma D006801:Humans D051795:Hypoxia-Inducible Factor 1, alpha Subunit D064799:Hypoxia-Inducible Factor-Proline Dioxygenases D007797:Laminin D009361:Neoplasm Invasiveness D011509:Proteoglycans D011839:Radiation, Ionizing D013997:Time Factors D044767:Ubiquitin-Protein Ligases D051794:Von Hippel-Lindau Tumor Suppressor Protein D048051:p38 Mitogen-Activated Protein Kinases
p38 MAPK Angiogenesis Infiltration of glioma cells Ionizing radiation Hypoxia inducible factor 1 alpha