title: The macrophage migration inhibitory factor (MIF)-homologue D-dopachrome tautomerase is a therapeutic target in a murine melanoma model.
abstract: The macrophage migration inhibitory factor (MIF)-homologue D-dopachrome tautomerase (D-DT) recently has been described to have similar functions as MIF. However, the role of D-DT, as opposed to MIF, in tumor biology remains unknown. We hypothesized that D-DT could represent a target for therapeutic interventions in cancer. We analyzed the production of D-DT in the murine melanoma model B16F10 and the murine breast cancer model 4T1 by western blot and ELISA. D-DT was released by tumor cells both in vitro and in vivo. RT-PCR revealed the expression of the D-DT receptor CD74 on both tumor cell lines. Tumor bearing mice had higher serum levels of D-DT compared to healthy controls. Remarkably, knock-down of D-DT by siRNA reduced proliferation of B16F10 cells in BrDU-assay and rendered them more prone to apoptosis induction, as shown by flow cytometry. In vivo neutralization of D-DT by antibodies reduced tumor progression in the B16F10 subcutaneous syngeneic tumor model. In summary, we could show that D-DT and its receptor are expressed in the murine tumors B16F10 and 4T1. Knock-down of D-DT through siRNA or blocking by antibodies reduced proliferation of B16F10 tumor cells. This qualifies D-DT for further evaluation as a therapeutic target.
authors.affiliation: Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Internal Medicine IV, Ludwig-Maximilians-Universität München, Munich, Germany, Member of the German Center for Lung Research.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kobold
authors.forename: Melanie
authors.initials: M
authors.lastname: Merk
authors.forename: Luisa
authors.initials: L
authors.lastname: Hofer
authors.forename: Philip
authors.initials: P
authors.lastname: Peters
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.forename: Stefan
authors.initials: S
authors.lastname: Endres
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology; D045744:Cell Line, Tumor; D005260:Female; D055785:Gene Knockdown Techniques; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000628:therapy; D008546:Melanoma, Experimental / Q000201:enzymology* / Q000628:therapy*; D051379:Mice; D058990:Molecular Targeted Therapy; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics
chemical_list: D057134:Antibodies, Neutralizing; D034741:RNA, Small Interfering; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase