Carcinogenesis Advance Access published online on February 6, 2008
Carcinogenesis, doi:10.1093/carcin/bgn032
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Reactive Oxygen Species Stabilize Hypoxia Inducible Factor-1 Alpha Protein and Stimulate Transcriptional Activity via AMP-activated Protein Kinase in DU145 Human Prostate Cancer Cells
1 Department of Biochemistry and Molecular Biology, Kyung Hee University School of Medicine, Seoul 130-701, Korea
2 Department of Life Science, University of Seoul, Seoul 130-743, Korea
* To whom correspondence should be addressed: Tel: 82-2-961-0921; Fax: 82-959-8168; E-mail: hajh{at}khu.ac.kr. Tel: 82-2-961-0922; Fax: 82-2-965-6349; E-mail: iskang{at}khu.ac.kr.
Hypoxia-inducible factor (HIF-1) plays a central role in the cellular adaptive response to hypoxic conditions, which are closely related to patho-physiological conditions, such as cancer. Although reactive oxygen species (ROS) have been implicated in the regulation of hypoxic and non-hypoxic induction of HIF-1 under various conditions, the role of ROS is quite controversial, and the mechanism underlying the HIF-1 regulation by ROS is not completely understood yet. Here, we investigated the biochemical mechanism for the ROS-induced HIF-1 by revealing a novel role of AMP-activated protein kinase (AMPK) and the upstream signal components. AMPK plays an essential role as energy-sensor under ATP-deprived conditions. Here we report that ROS induced by a direct application of H2O2 and menadione to DU145 human prostate carcinoma resulted in accumulation of HIF-1
protein by attenuation of its degradation and activation of its transcriptional activity in an AMPK-dependent manner. By way of contrast, AMPK was required only for the transcriptional activity of HIF-1 under hypoxic condition, revealing a differential role of AMPK in these two stimuli. Furthermore, our data show that inhibition of AMPK enhances HIF-1 ubiquitination under ROS condition. Finally, we show that the regulation of HIF-1 by AMPK in response to ROS is under the control of c-Jun N-terminal kinase and Janus kinase 2 pathway. Collectively, our findings identify AMPK as a key determinant of HIF-1 functions in response to ROS and its possible role in the sophisticated HIF-1 regulatory mechanisms.
Received September 10, 2007; revised January 24, 2008; accepted January 26, 2008.
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