CYSLTR1 antagonism displays potent anti-tumor effects in uveal melanoma

• Published in: Experimental eye research 2024-11, Vol.248, p.110120, Article 110120
• Main Authors: García de Alba Graue, Paulina, Abdouh, Mohamed, Goyeneche, Alicia, Burnier, Julia Valdemarin, Burnier, Miguel N.
• Format: Article
• Language: English
• Subjects: Aged; Apoptosis - drug effects; Blotting, Western; Cell death; Cell growth; Cell Line, Tumor; Cell lines; Cell Proliferation - drug effects; Cell Survival - drug effects; CYSLTR1 expression; Female; Gene Expression Regulation, Neoplastic; Human specimens; Humans; Male; Melanoma - drug therapy; Melanoma - genetics; Melanoma - metabolism; Melanoma - pathology; Middle Aged; MK571 antagonism; Receptors, Leukotriene - genetics; Receptors, Leukotriene - metabolism; Tumor Cells, Cultured; Uveal melanoma; Uveal Neoplasms - drug therapy; Uveal Neoplasms - genetics; Uveal Neoplasms - metabolism; Uveal Neoplasms - pathology
• ISSN: 0014-4835; 1096-0007; 1096-0007
• DOI: 10.1016/j.exer.2024.110120

Uveal Melanoma (UM) is the most common primary intraocular malignancy in adults. Although rare, it is a deadly tumor, with a long-term prognosis of death occurring in more than 50% of the cases. It is characterized by frequent (∼80%) driver mutations in GNAQ and GNA11 genes, both of which are activated by cysteinyl leukotriene receptors (CYSLTRs). CYSLTR1 is upregulated and participated in the progression of several cancers. In the present study, we sought to determine the expression levels of CYSLTR1 in 31 human UM specimens and cell lines (3 primary and 1 metastatic), and its role in the proliferation and viability of these cells by analyzing cell metabolic activity, cell confluence and apoptosis levels. We show that all analyzed UM specimens and cells expressed CYSLTR1 at high levels. Notably, the pharmacological blockage of this receptor, using the inverse agonist MK571, reduced the growth and metabolic activity, and increased the apoptotic cell death of all analyzed UM cell lines. We provide evidence that CYSLTR1 is expressed in human UM and plays a significant role in UM progression behavior. Our data highlight the potential beneficial effects of targeting CYSLTR1 in the control of UM progression. •CYSLTR1 is highly expressed in human UM specimens.•CYSLTR1 is highly expressed in primary and metastatic human UM cell lines.•Antagonizing CYSLTR1 reduces the proliferation and viability of UM cells.