AMP-activated protein kinase activity is required for vanadate-induced hypoxia-inducible factor 1alpha expression in DU145 cells.

Abstract

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.

• Authors: Jin-Taek Hwang, Minyoung Lee, Seung-Nam Jung, Hye-Jeong Lee, Insug Kang, Sung-Soo Kim, Joohun Ha
• Journal: Carcinogenesis (Carcinogenesis) Vol. 25 Issue 12 Pg. 2497-507 (Dec 2004) ISSN: 0143-3334 [Print] England
• PMID: 15297373 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Multienzyme Complexes
• Proto-Oncogene Proteins
• RNA, Messenger
• RNA, Neoplasm
• Transcription Factors
• Vanadates
• Adenosine Triphosphate
• Protein Kinases
• MTOR protein, human
• AKT1 protein, human
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases
• Adenosine Triphosphate (metabolism)
• Cell Hypoxia
• Enzyme Activation
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit
• Male
• Multienzyme Complexes (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Prostatic Neoplasms (genetics, metabolism)
• Protein Kinases (metabolism)
• Protein Serine-Threonine Kinases (metabolism)
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-akt
• RNA, Messenger (genetics, metabolism)
• RNA, Neoplasm (genetics, metabolism)
• Signal Transduction
• TOR Serine-Threonine Kinases
• Transcription Factors (metabolism)
• Tumor Cells, Cultured
• Vanadates (adverse effects)