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

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.

Dexamethasone Promotes a Stem-Like Phenotype in Human Melanoma Cells via Tryptophan 2,3 Dioxygenase

“…Moreover, pretreatment of parental cells with 680C91 significantly abolished expression of these stemness markers in control unstimulated spheres, suggesting that TDO may regulate those genes in unstimulated cells as well. Our recently published report and this study clearly show that dex upregulates TDO (Cecchi et al, 2021), whose inhibition abrogated melanoma cell spherogenesis and suppressed the up-regulation of stem cell markers.…”

“…We recently showed that TDO is expressed in SK-Mel-28 cells, and that this expression is upregulated by dex with maximal effects achieved at 25 µM ( Cecchi et al, 2021 ). To test whether this expression is restricted to this cell line, we employed a more aggressive melanoma cell line, namely A375 ( Rossi et al, 2018 ).…”

“…Moreover, we and others have shown that it promotes growth, migration, and invasiveness of cancer cells, including melanomas (Pham QT. et al, 2021;Cecchi et al, 2021).…”

“…While TDO’s role in cancer immunosuppression is well-established ( Ye et al, 2019 ), its direct effects on tumor cells remain unclear. We previously demonstrated that the SK-Mel-28 human melanoma cell line possesses a functional TDO, which is up-regulated by dexamethasone (dex), a synthetic glucocorticoid (GC) widely used in cancer therapy ( Cecchi et al, 2021 ). Dex promoted SK-Mel-28 proliferation, migration, and invasiveness via TDO ( Cecchi et al, 2021 ), highlighting the controversial role of GC in cancer cell fate and the new possible implications of TDO in human melanoma.…”

“…We previously demonstrated that the SK-Mel-28 human melanoma cell line possesses a functional TDO, which is up-regulated by dexamethasone (dex), a synthetic glucocorticoid (GC) widely used in cancer therapy ( Cecchi et al, 2021 ). Dex promoted SK-Mel-28 proliferation, migration, and invasiveness via TDO ( Cecchi et al, 2021 ), highlighting the controversial role of GC in cancer cell fate and the new possible implications of TDO in human melanoma. Melanomas arise from mature, differentiated melanocytes as well as from tumor stem cells that can self-renew and promote incessant growth ( Reya et al, 2001 ).…”