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* The Bay Pines Veterans Affairs Healthcare System, Research and Development, Bay Pines, FL 33744;
University of South Florida, Department of Surgery, Tampa, FL 33612;
Malcom Randall Veterans Affairs Medical Center, Department of Pathology, Gainesville, FL 32608;
University of Florida College of Medicine, Department of Pathology, Immunology, and Laboratory Medicine, Gainesville, FL 32610; and
¶ Yale University School of Medicine, New Haven, CT 06520
Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, is overexpressed in prostate cancer, but the mechanism by which MIF exerts effects on tumor cells remains undetermined. MIF interacts with its identified membrane receptor, CD74, in association with CD44, resulting in ERK 1/2 activation. Therefore, we hypothesized that increased expression or surface localization of CD74 and MIF overexpression by prostate cancer cells regulated tumor cell viability. Prostate cancer cell lines (LNCaP and DU-145) had increased MIF gene expression and protein levels compared with normal human prostate or benign prostate epithelial cells (p < 0.01). Although MIF, CD74, and CD44 variant 9 expression were increased in both androgen-dependent (LNCaP) and androgen-independent (DU-145) prostate cancer cells, cell surface of CD74 was only detected in androgen-independent (DU-145) prostate cancer cells. Therefore, treatments aimed at blocking CD74 and/or MIF (e.g., inhibition of MIF or CD74 expression by RNA interference or treatment with anti-MIF- or anti-CD74- neutralizing Abs or MIF-specific inhibitor, ISO-1) were only effective in androgen-independent prostate cancer cells (DU-145), resulting in decreased cell proliferation, MIF protein secretion, and invasion. In DU-145 xenografts, ISO-1 significantly decreased tumor volume and tumor angiogenesis. Our results showed greater cell surface CD74 in DU-145 prostate cancer cells that bind to MIF and, thus, mediate MIF-activated signal transduction. DU-145 prostate cancer cell growth and invasion required MIF activated signal transduction pathways that were not necessary for growth or viability of androgen-dependent prostate cells. Thus, blocking MIF either at the ligand (MIF) or receptor (CD74) may provide new, targeted specific therapies for androgen-independent prostate cancer.
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 Supported by Veterans Affairs Merit Review Program (to K.L.M.-S. and P.L.V.), the Bay Pines Foundation (to K.L.M.-S. and P.L.V.), and National Institutes of Health (to R.B. and L.L.).
2 Address correspondence and reprint requests to Dr. Katherine L. Meyer-Siegler, Bay Pines Veterans Affairs Health Care System, Research and Development (151), 10000 Bay Pines Boulevard, Bay Pines, FL 33744. E-mail address: Katherine.Siegler{at}med.va.gov
3 Abbreviations used in this paper: MIF, macrophage inhibitory factor; CD44v9, CD44 variant 9; PrEC, human prostate epithelial cells; PVDF, polyvinylidene difluoride; RNAi, RNA interference; PCNA, proliferating cell nuclear Ag; p-ERK, phosphorylated ERK; pNA, p-nitroaniline.
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