Dexamethasone Induces the Expression and Function of Tryptophan-2-3-Dioxygenase in SK-MEL-28 Melanoma Cells
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 melano...
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MDPI AG
2021-03-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/14/3/211 |
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| author | Marta Cecchi Sara Paccosi Angela Silvano Ali Hussein Eid Astrid Parenti |
| author_facet | Marta Cecchi Sara Paccosi Angela Silvano Ali Hussein Eid Astrid Parenti |
| author_sort | Marta Cecchi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T05:39:04Z |
| format | Article |
| id | doaj.art-837bb033f0404de39ae18850bec583ad |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T05:39:04Z |
| publishDate | 2021-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-837bb033f0404de39ae18850bec583ad2023-12-03T12:26:32ZengMDPI AGPharmaceuticals1424-82472021-03-0114321110.3390/ph14030211Dexamethasone Induces the Expression and Function of Tryptophan-2-3-Dioxygenase in SK-MEL-28 Melanoma CellsMarta Cecchi0Sara Paccosi1Angela Silvano2Ali Hussein Eid3Astrid Parenti4Department of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, Viale Pieraccini 6, 50139 Florence, ItalyDepartment of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, Viale Pieraccini 6, 50139 Florence, ItalyDepartment of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, Viale Pieraccini 6, 50139 Florence, ItalyDepartment of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, QatarDepartment of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, Viale Pieraccini 6, 50139 Florence, ItalyTryptophan-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.https://www.mdpi.com/1424-8247/14/3/211SK-Mel-28melanomatryptophan-2,3-dioxygenaseindoleamine-2,3-dioxygenase-1dexamethasone680C91 |
| spellingShingle | Marta Cecchi Sara Paccosi Angela Silvano Ali Hussein Eid Astrid Parenti Dexamethasone Induces the Expression and Function of Tryptophan-2-3-Dioxygenase in SK-MEL-28 Melanoma Cells Pharmaceuticals SK-Mel-28 melanoma tryptophan-2,3-dioxygenase indoleamine-2,3-dioxygenase-1 dexamethasone 680C91 |
| title | Dexamethasone Induces the Expression and Function of Tryptophan-2-3-Dioxygenase in SK-MEL-28 Melanoma Cells |
| title_full | Dexamethasone Induces the Expression and Function of Tryptophan-2-3-Dioxygenase in SK-MEL-28 Melanoma Cells |
| title_fullStr | Dexamethasone Induces the Expression and Function of Tryptophan-2-3-Dioxygenase in SK-MEL-28 Melanoma Cells |
| title_full_unstemmed | Dexamethasone Induces the Expression and Function of Tryptophan-2-3-Dioxygenase in SK-MEL-28 Melanoma Cells |
| title_short | Dexamethasone Induces the Expression and Function of Tryptophan-2-3-Dioxygenase in SK-MEL-28 Melanoma Cells |
| title_sort | dexamethasone induces the expression and function of tryptophan 2 3 dioxygenase in sk mel 28 melanoma cells |
| topic | SK-Mel-28 melanoma tryptophan-2,3-dioxygenase indoleamine-2,3-dioxygenase-1 dexamethasone 680C91 |
| url | https://www.mdpi.com/1424-8247/14/3/211 |
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