The macrophage migration inhibitory factor (MIF)-homologue D-dopachrome tautomerase is a therapeutic target in a murine melanoma model

Sebastian Kobold,Philip Peters,Melanie Merk,Richard Bucala,Stefan Endres,Luisa Hofer

doi:10.18632/oncotarget.1560

Sebastian Kobold, Philip Peters + Show 4 more

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https://doi.org/10.18632/oncotarget.1560

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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.

Highlights

The macrophage migration inhibitory factor (MIF) was one of the first cytokines to be described and has since been implicated in many diseases including infectious diseases and cancer [1]
We show for the first time that D- dopachrome tautomerase (D-DT) has a proliferative and anti-apoptotic effect on B16F10 melanoma cells and that targeting of D-DT through siRNA or polyclonal D-DT antibodies may slow tumor progression in this model
D-DT expression so far has been evaluated in healthy tissues and only a few cancer models such as lung and colon cancer

Summary

Introduction

The macrophage migration inhibitory factor (MIF) was one of the first cytokines to be described and has since been implicated in many diseases including infectious diseases and cancer [1]. We and others have described functional overlaps between MIF and D-DT [4,5,6]. Both MIF and D-DT bind to the receptor CD74 and induce ERK1/2 phosphorylation, leading to macrophage migration arrest and counterregulation of glucocorticoid-induced immunosuppression [4]. Both MIF and D-DT contribute to CXCL8 and VEGF production, two important factors for tumor progression and angiogenesis [5]. Together with the finding that D-DT, as MIF, induces COX-2 expression through stabilization of β-catenin [6], these findings are strongly suggestive of a pro-tumorigenic role of D-DT, as previously demonstrated for MIF [7]

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