title: Amplification of tumor hypoxic responses by macrophage migration inhibitory factor-dependent hypoxia-inducible factor stabilization.
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.
authors.affiliation: Molecular Targets Program, James Graham Brown Cancer Center and Department of Radiation Oncology, University of Louisville, 580 South Preston Street, Louisville, KY, USA.
authors.forename: Millicent
authors.initials: M
authors.lastname: Winner
authors.forename: Albert C
authors.initials: AC
authors.lastname: Koong
authors.forename: Beatriz E
authors.initials: BE
authors.lastname: Rendon
authors.forename: Wayne
authors.initials: W
authors.lastname: Zundel
authors.forename: Robert A
authors.initials: RA
authors.lastname: Mitchell
mesh_terms: D000230:Adenocarcinoma / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000075686:COP9 Signalosome Complex; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008263:Macrophage Migration-Inhibitory Factors / Q000096:biosynthesis / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008263:Macrophage Migration-Inhibitory Factors; D046912:Multiprotein Complexes; D010447:Peptide Hydrolases; D000075686:COP9 Signalosome Complex