Journal Article

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

Jin-Taek Hwang, Minyoung Lee, Seung-Nam Jung, Hye-Jeong Lee, Insug Kang, Sung-Soo Kim and Joohun Ha

in Carcinogenesis

Volume 25, issue 12, pages 2497-2507
Published in print December 2004 | ISSN: 0143-3334
Published online December 2004 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgh253
AMP-activated protein kinase activity is required for vanadate-induced hypoxia-inducible factor 1α expression in DU145 cells

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Hypoxia-inducible factor 1 (HIF-1), a pivotal transcription factor composed of HIF-1α and HIF-1β 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-1α expression. Under this condition, inhibition of AMPK by a pharmacological and molecular approach dramatically abolished the vanadate-induced HIF-1α 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-1α 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.

Keywords: ACC, acetyl-CoA carboxylase; AICAR, 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside; AMPK, AMP-activated protein kinase; DCFH-DA, 2′,7′-dichlorofluorescein-diacetate; DN, dominant negative; ELISA, enzyme-linked immunosorbent assay; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; Glut, glucose transporter; HIF-1, hypoxia-inducible factor 1; MAP, mitogen-activated protein; mTOR, mammalian target of rapamycin; PI, phosphatidylinositol; PFKFB, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase; ROS, reactive oxygen species; RT, reverse transcriptase; VEGF, vascular endothelial growth factor; WT, wild-type

Journal Article.  6944 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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