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Cooperative Regulation of Non-Small Cell Lung Carcinoma Angiogenic Potential by Macrophage Migration Inhibitory Factor and Its Homolog, D-Dopachrome Tautomerase¹

Arlixer M. Coleman^*, Beatriz E. Rendon, Ming Zhao, Ming-Wei Qian, Richard Bucala, Dan Xin and Robert A. Mitchell^2,,

^* Microbiology and Immunology Program, School of Medicine, Biochemistry and Molecular Biology, School of Medicine, and Molecular Targets Program, J. G. Brown Cancer Center, University of Louisville, Louisville, KY 40202; and Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520

Tumor-derived growth factors and cytokines stimulate neoangiogenesis from surrounding capillaries to support tumor growth. Recent studies have revealed that macrophage migration inhibitory factor (MIF) expression is increased in lung cancer, particularly non-small cell lung carcinomas (NSCLC). Because MIF has important autocrine effects on normal and transformed cells, we investigated whether autocrine MIF and its only known family member, D-dopachrome tautomerase (D-DT), promote the expression of proangiogenic factors CXCL8 and vascular endothelial growth factor in NSCLC cells. Our results demonstrate that the expression of CXCL8 and vascular endothelial growth factor are strongly reliant upon both the individual and cooperative activities of the two family members. CXCL8 transcriptional regulation by MIF and D-DT appears to involve a signaling pathway that includes the activation of JNK, c-jun phosphorylation, and subsequent AP-1 transcription factor activity. Importantly, HUVEC migration and tube formation induced by supernatants from lung adenocarcinoma cells lacking either or both MIF and D-DT are substantially reduced when compared with normal supernatants. Finally, we demonstrate that the cognate MIF receptor, CD74, is necessary for both MIF- and D-DT-induced JNK activation and CXCL8 expression, suggesting its potential involvement in angiogenic growth factor expression. This is the first demonstration of a biological role for D-DT, and its synergism with MIF suggests that the combined therapeutic targeting of both family members may enhance current anti-MIF-based therapies.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by National Institutes of Health CA102285-S (to A.M.C.), National Institutes of Health CA102285 (to R.A.M.), National Institutes of Health AI042310 (to R.B.), and a grant from Philip Morris USA and Philip Morris International (to R.A.M.).

² Address correspondence and reprint requests to Dr. Robert A. Mitchell, University of Louisville, Delia Baxter Research Building, Suite 204B, 580 South Preston Street, Louisville, KY 40202. E-mail address: robert.mitchell{at}louisville.edu

³ Abbreviations used in this paper: NSCLC, non-small cell lung carcinoma; D-DT, D-dopachrome tautomerase; HIF, hypoxia-inducible factor; MIF, migration inhibitory factor; SCLC, small cell lung carcinoma; siRNA, small interfering RNA; VEGF, vascular endothelial growth factor.