1. Proc Natl Acad Sci U S A. 2010 Nov 23;107(47):20477-82. Epub 2010 Nov 8.

NADPH oxidase-mediated reactive oxygen species production activates
hypoxia-inducible factor-1 (HIF-1) via the ERK pathway after hyperthermia
treatment.

Moon EJ, Sonveaux P, Porporato PE, Danhier P, Gallez B, Batinic-Haberle I, Nien
YC, Schroeder T, Dewhirst MW.

Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.

Hyperthermia (HT) is a strong adjuvant treatment with radiotherapy and
chemotherapy because it causes tumor reoxygenation. However, the detailed
molecular mechanisms of how HT enhances tumor oxygenation have not been
elucidated. Here we report that 1 h of HT activates hypoxia-inducible factor-1
(HIF-1) in tumors and its downstream targets, vascular endothelial growth factor 
(VEGF) and pyruvate dehydrogenase kinase 1 (PDK1). Consistent with HIF-1
activation and up-regulation of its downstream genes, HT also enhances tumor
perfusion/vascularization and decreases oxygen consumption. As a result, tumor
hypoxia is reduced after HT, suggesting that these physiological changes
contribute to HT-induced tumor reoxygenation. Because HIF-1 is a potent regulator
of tumor vascularization and metabolism, our findings suggest that HIF-1 plays a 
role in HT-induced tumor reoxygenation by transactivating its downstream targets.
We demonstrate that NADPH oxidase-mediated reactive oxygen species production, as
a mechanism, up-regulates HIF-1 after HT. Furthermore, we determine that this
pathway is initiated by increased transcription of NADPH oxidase-1 through the
ERK pathway. In conclusion, this study determines that, although HIF-1 is a good 
therapeutic target, the timing of its inhibition needs to be optimized to achieve
the most beneficial outcome when it is combined with other treatments of HT,
radiation, and chemotherapy.


PMCID: PMC2996638 [Available on 2011/5/23]
PMID: 21059928 [PubMed - in process]