期刊
PHARMACEUTICALS
卷 14, 期 3, 页码 -出版社
MDPI
DOI: 10.3390/ph14030211
关键词
SK-Mel-28; melanoma; tryptophan-2,3-dioxygenase; indoleamine-2,3-dioxygenase-1; dexamethasone; epacadostat; migration; proliferation; MMP2
资金
- University of Florence
The study found that dexamethasone can up-regulate TDO and its downstream effector AHR, as well as promote cell proliferation and migration in melanoma cells, indicating that TDO may be a promising target for the treatment of melanoma progression.
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.
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