Abstract
Tryptophan-2,3-dioxygenase (TDO) is one of the key tryptophan-catabolizing enzymes with immunoregulatory properties in cancer. Contrary to expectation, clinical trials showed that inhibitors of the ubiquitously expressed enzyme, indoleamine-2,3-dioxygenase-1 (IDO1), do not provide benefits in melanoma patients. This prompted the hypothesis that TDO may be a more attractive target. Because the promoter of TDO harbors glucocorticoid response elements (GREs), we aimed to assess whether dexamethasone (dex), a commonly used glucocorticoid, modulates TDO expression by means of RT-PCR and immunofluorescence and function by assessing cell proliferation and migration as well as metalloproteinase activity. Our results show that, in SK-Mel-28 melanoma cells, dex up-regulated TDO and its downstream effector aryl hydrocarbon receptor (AHR) but not IDO1. Furthermore, dex stimulated cellular proliferation and migration and potentiated MMP2 activity. These effects were inhibited by the selective TDO inhibitor 680C91 and enhanced by IDO1 inhibitors. Taken together, our results demonstrate that the metastatic melanoma cell line SK-Mel-28 possesses a functional TDO which can also modulate cancer cell phenotype directly rather than through immune suppression. Thus, TDO appears to be a promising, tractable target in the management or the treatment of melanoma progression.
Highlights
L-tryptophan (Trp) is an essential amino acid that plays important roles in protein synthesis as well as the biosynthesis of melatonin, serotonin, and nicotinamide adenine dinucleotide (NAD+ ) [1]
A better understanding of the role of the immune system in cancer has led to the approval of several immunotherapies using monoclonal antibodies against immune checkpoints, such as ipilimumab as well as nivolumab and pembrolizumab [4]
Since TDO promotor harbors glucocorticoid response elements (GREs), we wished to determine the effect of dexamethasone on its expression in SK-Mel-28 cells
Summary
L-tryptophan (Trp) is an essential amino acid that plays important roles in protein synthesis as well as the biosynthesis of melatonin, serotonin, and nicotinamide adenine dinucleotide (NAD+ ) [1]. The role of Trp catabolism in cancer biology has been receiving increased interest due to its implication in cancer immune evasion [2]. Most Trp are catabolized by IDO1, which is ubiquitously expressed and can be induced by interferon gamma (IFN-γ) [3]. IDO1 has been widely demonstrated to possess immunosuppressive functions, which are established to correlate with poor survival in various cancer patients [2] (Figure 1). A better understanding of the role of the immune system in cancer has led to the approval of several immunotherapies using monoclonal antibodies against immune checkpoints, such as ipilimumab (anti CTLA-4) as well as nivolumab and pembrolizumab (anti PD-1) [4]. Only specific subgroups of patients responded to these immunotherapies, pointing out IDO1 as a further ideal candidate [3]
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