Dexamethasone Induces the Expression and Function of Tryptophan-2-3-Dioxygenase in SK-MEL-28 Melanoma Cells

被引:8
作者
Cecchi, Marta [1 ]
Paccosi, Sara [1 ]
Silvano, Angela [1 ]
Eid, Ali Hussein [2 ,3 ]
Parenti, Astrid [1 ]
机构
[1] Univ Florence, Dept Hlth Sci, Clin Pharmacol & Oncol Sect, Viale Pieraccini 6, I-50139 Florence, Italy
[2] Qatar Univ, Dept Basic Med Sci, Coll Med, QU Hlth, POB 2713, Doha, Qatar
[3] Qatar Univ, Biomed & Pharmaceut Res Unit, QU Hlth, POB 2713, Doha, Qatar
关键词
SK-Mel-28; melanoma; tryptophan-2,3-dioxygenase; indoleamine-2,3-dioxygenase-1; dexamethasone; epacadostat; migration; proliferation; MMP2; HYDROCARBON RECEPTOR AHR; CHEMOTHERAPY RESISTANCE; EXTRACELLULAR-MATRIX; ANTITUMOR AGENTS; UP-REGULATION; INHIBITION; BREAST; GLUCOCORTICOIDS; PROLIFERATION; IMMUNOTHERAPY;
D O I
10.3390/ph14030211
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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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页数:16
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