title: 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.
authors.affiliation: Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul 133-791, Republic of Korea.
authors.forename: Young-Heon
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul 133-791, Republic of Korea.
authors.forename: Ki-Chun
authors.initials: KC
authors.lastname: Yoo
authors.affiliation: Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul 133-791, Republic of Korea.
authors.forename: Yan-Hong
authors.initials: YH
authors.lastname: Cui
authors.affiliation: Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul 133-791, Republic of Korea.
authors.forename: Nizam
authors.initials: N
authors.lastname: Uddin
authors.affiliation: Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul 133-791, Republic of Korea.
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Lim
authors.affiliation: Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea.
authors.forename: Min-Jung
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Radiation Health Research Institute, Korea Hydro & Nuclear Power Co. LTD., Seoul 132-703, Republic of Korea.
authors.forename: Seon-Young
authors.initials: SY
authors.lastname: Nam
authors.affiliation: Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, Daejeon 305-600, Republic of Korea.
authors.forename: In-Gyu
authors.initials: IG
authors.lastname: Kim
authors.affiliation: Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul 133-791, Republic of Korea. Electronic address: hiswork@hanmail.net.
authors.forename: Yongjoon
authors.initials: Y
authors.lastname: Suh
authors.affiliation: Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul 133-791, Republic of Korea. Electronic address: sj0420@hanyang.ac.kr.
authors.forename: Su-Jae
authors.initials: SJ
authors.lastname: Lee
mesh_terms: D001932:Brain Neoplasms / Q000378:metabolism* / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D002465:Cell Movement; D003094:Collagen / Q000737:chemistry; D018450:Disease Progression; D019583:Dose Fractionation, Radiation; D004338:Drug Combinations; D005910:Glioma / Q000378:metabolism* / Q000532:radiotherapy*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000378:metabolism; D007797:Laminin / Q000737:chemistry; D009361:Neoplasm Invasiveness; D011509:Proteoglycans / Q000737:chemistry; D011839:Radiation, Ionizing; D013997:Time Factors; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D004338:Drug Combinations; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen; C490190:EGLN1 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D048051:p38 Mitogen-Activated Protein Kinases; C497446:VHL protein, human
keywords: Angiogenesis; Hypoxia inducible factor 1 alpha; Infiltration of glioma cells; Ionizing radiation; p38 MAPK