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

Marta Cecchi; Antonella Mannini; Andrea Lapucci; Angela Silvano; Matteo Lulli; Cristina Luceri; Mario D'Ambrosio; Alberto Chiarugi; Ali H Eid; Astrid Parenti

doi:10.3389/fphar.2022.911019

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

Front Pharmacol. 2022 Jun 30:13:911019. doi: 10.3389/fphar.2022.911019. eCollection 2022.

Authors

Affiliations

¹ Department of Neuroscience, Psychology, Drug Research and Child Health, Neurofarba, Pharmacology and Toxicology Section, University of Florence, Florence, Italy.
² Department of Experimental and Clinical Medicine, Internal Medicine Section, University of Florence, Florence, Italy.
³ Department of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, Florence, Italy.
⁴ Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.
⁵ Department of Basic Medical Sciences, Qatar University, QU Health, Doha, Qatar.

Abstract

In addition to its well-established immunosuppressive actions, tryptophan 2,3-dioxygenase (TDO) appears to elicit direct effects on tumor cell function. Although TDO has been associated with cancer stemness, its involvement in melanoma stem cell biology remains largely unknown. Since we showed that by upregulating TDO, dexamethasone (dex) promotes proliferation and migration of SK-Mel-28 human melanoma cells, we sought to investigate dex effects on melanoma spherogenesis and stemness, and whether these events are mediated by TDO. We demonstrate here that dex significantly upregulates TDO in A375, a more aggressive melanoma cell line, confirming that dex effects are not limited to SK-Mel-28 cells. Moreover, dex stimulates spherogenesis of both cell lines, which is mediated by TDO, evident by its suppression with 680C91, a TDO inhibitor. The formed melanospheres appear to be enriched with embryonic stem cell marker mRNAs, the expression of which is potentiated by dex. Expression of cancer stem cell markers (CD133, CD44, ganglioside GD2) was significantly increased in A375 spheres, as detected by flow cytometry. Taken together, our results suggest that TDO could represent a promising target in the management of melanoma and that dex, routinely used as a co-medication also in advanced melanoma, may stimulate melanoma cell function/tumor-supporting properties, a rather debilitating and undesired side effect.

Keywords: A375; SK-MEL-28; dexamethasone; embryonic stem cell markers; glucocorticoids; melanoma; melanospheres; tryptophan 2,3 dioxygenase.