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Amplification of Tumor Hypoxic Responses by Macrophage Migration Inhibitory Factor–Dependent Hypoxia-Inducible Factor Stabilization

¹ Molecular Targets Program, James Graham Brown Cancer Center and Department of Radiation Oncology, University of Louisville, Louisville, Kentucky and ² Department of Radiation Oncology, Stanford University, Stanford, California

Requests for reprints: Robert A. Mitchell, University of Louisville, Suite 204B, Delia Baxter Research Building, 580 South Preston Street, Louisville, KY. Phone: 502-852-7698; Fax: 502-852-5679; E-mail: robert.mitchell{at}louisville.edu.

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-1 expression. Cells lacking MIF are defective in hypoxia- and prolyl hydroxylase inhibitor–induced HIF-1 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-1. 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-1 interactions. This functional interdependence between HIF-1 and MIF may represent an important and previously unrecognized protumorigenic axis. [Cancer Res 2007;67(1):186–93]

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