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Dexamethasone Induces the Expression and Function of Tryptophan-2-3-Dioxygenase in SK-MEL-28 Melanoma Cells
Marta Cecchi1, Sara Paccosi1, Angela Silvano1
1Department of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
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.
Insights
Tryptophan-2,3-dioxygenase (TDO) is a promising target in melanoma. Dexamethasone up-regulated TDO and promoted melanoma cell growth and migration, suggesting TDO directly impacts cancer progression.
Area of Science:
- Biochemistry
- Cancer Biology
- Immunology
Background:
- Tryptophan-2,3-dioxygenase (TDO) is a key enzyme in tryptophan metabolism with immunoregulatory roles in cancer.
- Indoleamine-2,3-dioxygenase-1 (IDO1) inhibitors have shown limited efficacy in melanoma clinical trials, suggesting TDO as a potential alternative target.
- TDO's promoter contains glucocorticoid response elements (GREs), indicating potential regulation by glucocorticoids.
Purpose of the Study:
- To investigate whether dexamethasone (dex) modulates TDO expression and function in melanoma cells.
- To assess the impact of dexamethasone-induced TDO modulation on melanoma cell proliferation, migration, and metalloproteinase activity.
- To evaluate TDO as a potential therapeutic target for melanoma progression.
Main Methods:
- Reverse transcription-polymerase chain reaction (RT-PCR) to assess gene expression.
- Immunofluorescence to visualize protein expression.
- Cell proliferation and migration assays.
- Metalloproteinase (MMP2) activity assessment.
- Treatment with selective TDO inhibitor (680C91) and IDO1 inhibitors.
Main Results:
- Dexamethasone up-regulated TDO and aryl hydrocarbon receptor (AHR) expression in SK-Mel-28 melanoma cells, but not IDO1.
- Dexamethasone treatment stimulated melanoma cell proliferation and migration.
- Dexamethasone potentiated MMP2 activity, which was reversed by a TDO inhibitor.
- IDO1 inhibitors enhanced the effects of dexamethasone.
Conclusions:
- The metastatic melanoma cell line SK-Mel-28 exhibits functional TDO.
- Dexamethasone modulates TDO expression and directly influences melanoma cell phenotype, including proliferation, migration, and MMP2 activity.
- TDO is a promising and tractable therapeutic target for managing melanoma progression, potentially acting independently of immune suppression.
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