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: Sebastian Kobold, Melanie Merk, Luisa Hofer, Philip Peters, Richard Bucala, Stefan Endres
• Journal: Oncotarget (Oncotarget) Vol. 5 Issue 1 Pg. 103-7 (Jan 15 2014) ISSN: 1949-2553 [Electronic] United States
• PMID: 24406307 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Neutralizing
• RNA, Small Interfering
• Intramolecular Oxidoreductases
• dopachrome isomerase

Topics

• Animals
• Antibodies, Neutralizing (immunology, pharmacology)
• Cell Line, Tumor
• Female
• Gene Knockdown Techniques
• Intramolecular Oxidoreductases (biosynthesis, genetics, immunology)
• Mammary Neoplasms, Experimental (enzymology, therapy)
• Melanoma, Experimental (enzymology, therapy)
• Mice
• Molecular Targeted Therapy
• RNA, Small Interfering (administration & dosage, genetics)