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Inhibition of macrophage migration inhibitory factor or its receptor (CD74) attenuates growth and invasion of DU-145 prostate cancer cells. J Immunol 2006 Dec 15;177(12):8730-9

Date

12/05/2006

Pubmed ID

17142775

DOI

10.4049/jimmunol.177.12.8730

Scopus ID

2-s2.0-33845418379   173 Citations

Abstract

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.

Author List

Meyer-Siegler KL, Iczkowski KA, Leng L, Bucala R, Vera PL

Author

Kenneth A. Iczkowski MD Professor in the Pathology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Antigens, Differentiation, B-Lymphocyte
Cell Line, Tumor
Cell Proliferation
Histocompatibility Antigens Class II
Humans
Intramolecular Oxidoreductases
Isoxazoles
Macrophage Migration-Inhibitory Factors
Male
Mice
Neoplasm Invasiveness
Neoplasm Proteins
Prostatic Neoplasms
Signal Transduction
Transplantation, Heterologous
jenkins-FCD Prod-399 190a069c593fb5498b7fcd942f44b7bc9cdc7ea1