Carcinogenesis Advance Access published online on August 5, 2004
Carcinogenesis, doi:10.1093/carcin/bgh253
© 2004 by Oxford University Press
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1 Department of Biochemistry and Molecular Biology, Medical Research Center for Bioreaction to Reactive Oxygen Species, Kyung Hee University College of Medicine, Seoul 130-701, Korea
* To whom correspondence should be addressed. E-mail: hajh{at}khu.ac.kr.
Hypoxia-inducible factor 1 (HIF-1), a pivotal transcription factor composed of HIF-1
Revised July 22, 2004
Accepted July 25, 2004
CARCINOGENESIS
AMP-activated protein kinase activity is required for vanadate-induced hypoxia-inducible factor 1
expression in DU145 cells
2 Department of Pharmacology, Medical Research Center for Cancer Molecular Therapy, Dong-A University, Busan, 602-103, Korea
Abstract 
and HIF-1
subunits, plays a major role in tumor progression by activating a number of genes critically involved in adaptation to hypoxia. HIF-1 is also induced by several carcinogenic metals. Vanadate, an environmental toxic metal, is considered as a potent inducer of tumors in animals and is reported to activate HIF-1 activity. However, the involved mechanisms are poorly understood. In the present study, we have examined the biochemical mechanisms of the vanadate-induced HIF-1 activation in cancer cells by primarily focusing on the role of AMP-activated protein kinase (AMPK), which plays an essential role as an energy-sensor under ATP-deprived conditions. We demonstrate that AMPK was rapidly activated in response to vanadate in DU145 human prostate carcinoma, and that its activation preceded HIF-1 expression. Under the condition, inhibition of AMPK by a pharmacological and molecular approach dramatically abolished the vanadate-induced HIF-1 expression as well as HIF-1-mediated physiological responses. Phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin signaling was also involved in vanadate-induced HIF-1 expression, but it was independent of AMPK signaling pathway. Moreover, we demonstrate a role of reactive oxygen species as an upstream signal for these two pathways. These results suggest that AMPK is a novel and critical component of HIF-1 regulation, further implying its involvement in vanadate-induced carcinogenesis.
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