Amplification of Tumor Hypoxic Responses by Macrophage Migration Inhibitory Factor-dependent Hypoxia-inducible Factor Stabilization.
From: Molecular Targets Program, James Graham Brown Cancer Center and Department of Radiation Oncology, University of Louisville, 580 South Preston Street, Louisville, KY, USA.
Cancer research
- Publish Date: Jan 2007
- ISSN: 0008-5472
- Volume: 67
- Issue: 1
- Pages: 186-93
- Medium: Print
- Language: English
- Citation (JAMA): Winner Millicent, Koong Albert C, Rendon Beatriz E, et al. Amplification of Tumor Hypoxic Responses by Macrophage Migration Inhibitory Factor-dependent Hypoxia-inducible Factor Stabilization.. Cancer Res. Jan 2007;67:186-93
Abstract
Low oxygen tension-mediated transcription by hypoxia-inducible factors (HIF) has been reported to facilitate tumor progression, therapeutic resistance, and metastatic adaptation. One previously described target of hypoxia-mediated transcription is the cytokine/growth factor macrophage migration inhibitory factor (MIF). In studies designed to better understand hypoxia-stimulated MIF function, we have discovered that not only is MIF induced by hypoxia in pancreatic adenocarcinoma but MIF is also necessary for maximal hypoxia-induced HIF-1alpha expression. Cells lacking MIF are defective in hypoxia- and prolyl hydroxylase inhibitor-induced HIF-1alpha stabilization and subsequent transcription of glycolytic and angiogenic gene products. Moreover, COP9 signalosome subunit 5 (CSN5), a component of the COP9 signalosome previously reported to functionally interact with MIF, has recently been shown to interact with and stabilize HIF-1alpha. Our results indicate that MIF interacts with CSN5 in pancreatic cancer cells and that MIF-depleted cells display marked defects in hypoxia-induced CSN5/HIF-1alpha interactions. This functional interdependence between HIF-1alpha and MIF may represent an important and previously unrecognized pro-tumorigenic axis.
Mesh Headings (Keywords): Adenocarcinoma, Animals, Cell Hypoxia, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Macrophage Migration-Inhibitory Factors, Mice, Mice, Inbred C57BL, Multiprotein Complexes, Pancreatic Neoplasms, Peptide Hydrolases
Check for Full Text / PubMed Unique Identifier (PMID): 17210698
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