PMID- 21042761
OWN - NLM
STAT- MEDLINE
DCOM- 20110224
LR  - 20190606
IS  - 1791-2431 (Electronic)
IS  - 1021-335X (Linking)
VI  - 24
IP  - 6
DP  - 2010 Dec
TI  - Cycling hypoxia increases U87 glioma cell radioresistance via ROS induced higher 
      and long-term HIF-1 signal transduction activity.
PG  - 1629-36
AB  - Glioblastoma multiforme (GBM) tumors are the most common type of brain tumors and 
      resistance to radiotherapy. This study aimed to investigate the differential 
      effect and mechanism of tumor microenvironments, cycling hypoxia and 
      non-interrupted hypoxia, on tumor cell radiosensitivity in the human U87 
      glioblastoma tumor model. We exposed U87 cells and mice bearing U87 glioma to 
      experimentally imposed cycling or non-interrupted hypoxic stress in vitro and in 
      vivo prior to treatment with ionizing irradiation. Clonogenic survival assay and 
      tumor growth measurements were performed to determine tumor radiosensitivity. The 
      differential regulation of non-interrupted vs. cycling hypoxia by 
      hypoxia-inducible factor-1 (HIF-1) and the impact of HIF-1alpha on hypoxia-induced 
      radioresistance were assessed by molecular assay and RNAi-knockdown technology. 
      Our results demonstrated that cycling hypoxia induced higher and longer term 
      HIF-1 signal transduction activity via reactive oxygen species (ROS) in U87 cells 
      compared with non-interrupted hypoxia. Cycling hypoxia-induced HIF-1alpha activation 
      reflected ROS mediated HIF-1alpha synthesis and stabilization, whereas 
      non-interrupted hypoxia-induced HIF-1alpha activation was due to decreased HIF-1alpha 
      degradation resulting from decreased prolyl hydroxylation. With regard to tumor 
      radiosensitivity, cycling hypoxia induced more tumor cell radioresistance and a 
      decreased response to radiotherapy in U87 cells compared with non-interrupted 
      hypoxia. HIF-1 knockdown during in vitro and in vivo hypoxic stresses combined 
      with radiotherapy suppressed cycling and non-interrupted hypoxia-induced 
      radioresistance while increasing overall tumor radiosensitivity. Our results 
      suggest that cycling hypoxia induces more radioresistance than non-interrupted 
      hypoxia in U87 gliomas, and ROS mediated HIF-1alpha activation is a crucial mechanism 
      involved in hypoxia-induced differential radioresistant in U87 gliomas.
FAU - Hsieh, Chia-Hung
AU  - Hsieh CH
AD  - Graduate Institute of Basic Medical Science, Center for Neuropsychiatry, and 
      Graduate Institute of Immunology, China Medical University and Hospital, 
      Taichung, Taiwan, ROC. chhsiehcmu@mail.cmu.edu.tw
FAU - Lee, Cheng-Hung
AU  - Lee CH
FAU - Liang, Ji-An
AU  - Liang JA
FAU - Yu, Chun-Yen
AU  - Yu CY
FAU - Shyu, Woei-Cherng
AU  - Shyu WC
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Greece
TA  - Oncol Rep
JT  - Oncology reports
JID - 9422756
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Reactive Oxygen Species)
SB  - IM
MH  - Animals
MH  - Brain Neoplasms/*genetics/metabolism/*pathology
MH  - Cell Hypoxia/genetics/physiology
MH  - Cell Line, Tumor
MH  - Glioma/*genetics/metabolism/*pathology
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & 
      inhibitors/genetics/*metabolism
MH  - Mice
MH  - Oxygen Consumption/genetics/physiology
MH  - Periodicity
MH  - RNA, Small Interfering/pharmacology
MH  - Radiation Tolerance/drug effects/*genetics
MH  - Reactive Oxygen Species/metabolism/*pharmacology
MH  - Signal Transduction/genetics/physiology
MH  - Time Factors
MH  - Xenograft Model Antitumor Assays
EDAT- 2010/11/03 06:00
MHDA- 2011/02/25 06:00
CRDT- 2010/11/03 06:00
PHST- 2010/11/03 06:00 [entrez]
PHST- 2010/11/03 06:00 [pubmed]
PHST- 2011/02/25 06:00 [medline]
AID - 10.3892/or_00001027 [doi]
PST - ppublish
SO  - Oncol Rep. 2010 Dec;24(6):1629-36. doi: 10.3892/or_00001027.