PMID- 22713363
OWN - NLM
STAT- MEDLINE
DCOM- 20121221
LR  - 20220317
IS  - 1873-4596 (Electronic)
IS  - 0891-5849 (Linking)
VI  - 53
IP  - 4
DP  - 2012 Aug 15
TI  - NADPH oxidase subunit 4 mediates cycling hypoxia-promoted radiation resistance in 
      glioblastoma multiforme.
PG  - 649-58
LID - 10.1016/j.freeradbiomed.2012.06.009 [doi]
AB  - Cycling hypoxia is a well-recognized phenomenon within animal and human solid 
      tumors. It mediates tumor progression and radiotherapy resistance through 
      mechanisms that involve reactive oxygen species (ROS) production. However, 
      details of the mechanism underlying cycling hypoxia-mediated radioresistance 
      remain obscure. We have previously shown that in glioblastoma, NADPH oxidase 
      subunit 4 (Nox4) is a critical mediator involved in cycling hypoxia-mediated ROS 
      production and tumor progression. Here, we examined the impact of an in vivo 
      tumor microenvironment on Nox4 expression pattern and its impact on 
      radiosensitivity in GBM8401 and U251, two glioblastoma cell lines stably 
      transfected with a dual hypoxia-inducible factor-1 (HIF-1) signaling reporter 
      construct. Furthermore, in order to isolate hypoxic tumor cell subpopulations 
      from human glioblastoma xenografts based on the physiological and molecular 
      characteristics of tumor hypoxia, several techniques were utilized. In this 
      study, the perfusion marker Hoechst 33342 staining and HIF-1 activation labeling 
      were used together with immunofluorescence imaging and fluorescence-activated 
      cell sorting (FACS). Our results revealed that Nox4 was predominantly highly 
      expressed in the endogenous cycling hypoxic areas with HIF-1 activation and blood 
      perfusion within the solid tumor microenvironment. Moreover, when compared to the 
      normoxic or chronic hypoxic cells, the cycling hypoxic tumor cells derived from 
      glioblastoma xenografts have much higher Nox4 expression, ROS levels, and 
      radioresistance. Nox4 suppression in intracerebral glioblastoma-bearing mice 
      suppressed tumor microenvironment-mediated radioresistance and enhanced the 
      efficiency of radiotherapy. In summary, our findings indicated that cycling 
      hypoxia-induced Nox4 plays an important role in tumor microenvironment-promoted 
      radioresistance in glioblastoma; hence, targeting Nox4 may be an attractive 
      therapeutic strategy for blocking cycling hypoxia-mediated radioresistance.
CI  - Copyright (c) 2012 Elsevier Inc. All rights reserved.
FAU - Hsieh, Chia-Hung
AU  - Hsieh CH
AD  - Graduate Institute of Basic Medical Science, China Medical University, Taichung, 
      Taiwan. chhsiehcmu@mail.cmu.edu.tw
FAU - Wu, Chung-Pu
AU  - Wu CP
FAU - Lee, Hsu-Tung
AU  - Lee HT
FAU - Liang, Ji-An
AU  - Liang JA
FAU - Yu, Chun-Yen
AU  - Yu CY
FAU - Lin, Yu-Jung
AU  - Lin YJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120616
PL  - United States
TA  - Free Radic Biol Med
JT  - Free radical biology & medicine
JID - 8709159
RN  - 0 (Reactive Oxygen Species)
RN  - EC 1.13.12.- (Luciferases)
RN  - EC 1.6.3.- (NADPH Oxidase 4)
RN  - EC 1.6.3.- (NADPH Oxidases)
RN  - EC 1.6.3.- (NOX4 protein, human)
SB  - IM
MH  - Animals
MH  - Brain Neoplasms/*enzymology/pathology/radiotherapy
MH  - Cell Hypoxia
MH  - Cell Line, Tumor
MH  - Cell Survival/radiation effects
MH  - Gene Expression Regulation, Neoplastic
MH  - Gene Knockdown Techniques
MH  - Genes, Reporter
MH  - Glioblastoma/*enzymology/pathology/radiotherapy
MH  - Humans
MH  - Luciferases/biosynthesis/genetics
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - NADPH Oxidase 4
MH  - NADPH Oxidases/genetics/metabolism/*physiology
MH  - RNA Interference
MH  - *Radiation Tolerance
MH  - Reactive Oxygen Species
MH  - Tumor Microenvironment
MH  - Xenograft Model Antitumor Assays
EDAT- 2012/06/21 06:00
MHDA- 2012/12/22 06:00
CRDT- 2012/06/21 06:00
PHST- 2011/12/07 00:00 [received]
PHST- 2012/06/08 00:00 [revised]
PHST- 2012/06/08 00:00 [accepted]
PHST- 2012/06/21 06:00 [entrez]
PHST- 2012/06/21 06:00 [pubmed]
PHST- 2012/12/22 06:00 [medline]
AID - S0891-5849(12)00344-9 [pii]
AID - 10.1016/j.freeradbiomed.2012.06.009 [doi]
PST - ppublish
SO  - Free Radic Biol Med. 2012 Aug 15;53(4):649-58. doi: 
      10.1016/j.freeradbiomed.2012.06.009. Epub 2012 Jun 16.