title: AMP-activated protein kinase activity is critical for hypoxia-inducible factor-1 transcriptional activity and its target gene expression under hypoxic conditions in DU145 cells.
abstract: AMP-activated protein kinase (AMPK) functions as an energy sensor to provide metabolic adaptations under the ATP-deprived conditions such as hypoxia. In the present study, we considered a role of AMPK in the adaptive response to hypoxia by examining whether AMPK is involved in the regulation of hypoxia-inducible factor-1 (HIF-1), a heterodimeric transcription factor that is critical for hypoxic induction of physiologically important genes. We demonstrate that hypoxia or CoCl2 rapidly activated AMPK in DU145 human prostate cancer cells, and its activation preceded the induction of HIF-1 alpha expression. Under these conditions, blockade of AMPK activity by a pharmacological or molecular approach significantly attenuated hypoxia-induced responses such as HIF-1 target gene expression, secretion of vascular endothelial growth factor, glucose uptake, and HIF-1-dependent reporter gene expression, indicating that AMPK is critical for the HIF-1 transcriptional activity and its target gene expression. Its functional requirement for HIF-1 activity was also demonstrated in several different cancer cell lines, but AMPK activation alone was not sufficient to stimulate the HIF-1 transcriptional activity. We further present data showing that AMPK transmits a positive signal for HIF-1 activity via a signaling pathway that is independent of phosphatidylinositol 3-kinase/AKT and several mitogen-activated protein kinases. Taken together, our results suggest that AMPK is a novel and critical component of HIF-1 regulation, implying its new roles in oxygen-regulated cellular phenomena.
authors.affiliation: Department of Molecular Biology, Medical Research Center for Bioreaction to Reactive Oxygen Species, Kyung Hee University College of Medicine, Seoul, Korea.
authors.forename: Minyoung
authors.initials: M
authors.lastname: Lee
authors.forename: Jin-Taek
authors.initials: JT
authors.lastname: Hwang
authors.forename: Hye-Jeong
authors.initials: HJ
authors.lastname: Lee
authors.forename: Seung-Nam
authors.initials: SN
authors.lastname: Jung
authors.forename: Insug
authors.initials: I
authors.lastname: Kang
authors.forename: Sung-Gil
authors.initials: SG
authors.lastname: Chi
authors.forename: Sung-Soo
authors.initials: SS
authors.lastname: Kim
authors.forename: Joohun
authors.initials: J
authors.lastname: Ha
mesh_terms: D055372:AMP-Activated Protein Kinases; D001483:Base Sequence; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D003035:Cobalt / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D004789:Enzyme Activation; D015870:Gene Expression / Q000187:drug effects; D051272:Glucose Transporter Type 1; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000235:genetics; D009097:Multienzyme Complexes / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D051272:Glucose Transporter Type 1; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009004:Monosaccharide Transport Proteins; D009097:Multienzyme Complexes; D009687:Nuclear Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C495677:SLC2A1 protein, human; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D003035:Cobalt; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C018021:cobaltous chloride