AMP-activated protein kinase activity is required for vanadate-induced hypoxia-inducible factor 1alpha expression in DU145 cells.
Hypoxia-inducible factor 1 (HIF-1), a pivotal transcription factor composed of HIF-1alpha and HIF-1beta 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-1alpha expression. Under this condition, inhibition of AMPK by a pharmacological and molecular approach dramatically abolished the vanadate-induced HIF-1alpha 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-1alpha 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.
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.
Jin-Taek
JT
Hwang
Minyoung
M
Lee
Seung-Nam
SN
Jung
Hye-Jeong
HJ
Lee
Insug
I
Kang
Sung-Soo
SS
Kim
Joohun
J
Ha
D055372:AMP-Activated Protein Kinases; D000255:Adenosine Triphosphate / Q000378:metabolism; D015687:Cell Hypoxia; D004789:Enzyme Activation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008297:Male; D009097:Multienzyme Complexes / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014638:Vanadates / Q000009:adverse effects*
D055372:AMP-Activated Protein Kinases; D000255:Adenosine Triphosphate; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009097:Multienzyme Complexes; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; D014638:Vanadates; C497442:HIF1A protein, human; C546842:MTOR protein, human; C494918:AKT1 protein, human