Blockage of aquaporin‐3 peroxiporin activity by organogold compounds affects melanoma cell adhesion, proliferation and migration

• Published in: The Journal of physiology 2024-07, Vol.602 (13), p.3111-3129
• Main Authors: da Silva, Inês V., Pimpão, Catarina, Paccetti‐Alves, Inês, Thomas, Sophie R., Barateiro, Andreia, Casini, Angela, Soveral, Graça
• Format: Article
• Language: English
• Subjects: Antineoplastic drugs; Aquaporin 3; Aquaporin 3 - genetics; Aquaporin 3 - metabolism; Aquaporins; Cancer; cancer cells; Cancer therapies; Cell adhesion; Cell adhesion & migration; Cell Adhesion - drug effects; Cell Line, Tumor; Cell membranes; Cell migration; Cell Movement - drug effects; Cell proliferation; Cell Proliferation - drug effects; Erythrocytes; Glycerol; Gold; gold compounds; HEK293 Cells; Humans; Hydrogen peroxide; Hydrogen Peroxide - metabolism; Hydrogen Peroxide - pharmacology; Melanoma; Melanoma - drug therapy; Melanoma - metabolism; Melanoma - pathology; Permeability; Phenotypes; Toxicity; Tumor cell lines
• ISSN: 0022-3751; 1469-7793; 1469-7793
• DOI: 10.1113/JP284155

Aquaporin‐3 (AQP3) is a membrane channel with dual aquaglyceroporin/peroxiporin activity, facilitating the diffusion of water, glycerol and H2O2 across cell membranes. AQP3 shows aberrant expression in melanoma and its role in cell adhesion, migration and proliferation is well described. Gold compounds were shown to modulate AQP3 activity with reduced associated toxicity, making them promising molecules for cancer therapy. In this study, we validated the phenotype resulting from AQP3‐silencing of two melanoma cell lines, MNT‐1 and A375, which resulted in decreased H2O2 permeability. Subsequently, the AQP3 inhibitory effect of a new series of organogold compounds derived from Auphen, a potent AQP3 inhibitor, was first evaluated in red blood cells (RBCs) that highly express AQP3, and then in HEK‐293T cells with AQP3 overexpression to ascertain the compounds’ specificity. The first screening in RBCs unveiled two organogold compounds as promising blockers of AQP3 permeability. Moderate reduction of glycerol permeability but drastic inhibition of H2O2 permeability was detected for some of the gold derivatives in both AQP3‐overexpressing cells and human melanoma cell lines. Additionally, all compounds were effective in impairing cell adhesion, proliferation and migration, although in a cell type‐dependent manner. In conclusion, our data show that AQP3 peroxiporin activity is crucial for melanoma progression and highlight organogold compounds as promising AQP3 inhibitors with implications in melanoma cell adhesion, proliferation and migration, unveiling their potential as anticancer drugs against AQP3‐overexpressing tumours. Key points AQP3 affects cellular redox balance. Gold compounds inhibit AQP3 permeability in melanoma cells. AQP3 is involved in cell adhesion, proliferation and migration of melanoma. Blockage of AQP3 peroxiporin activity impairs melanoma cell migration. Gold compounds are potential anticancer drug leads for AQP3‐overexpressing cancers. figure legend AQP3 peroxiporin activity is modulated by organogold compounds. Reduced AQP3 permeability correlates with impaired cell adhesion, proliferation and migration of melanoma cells. Organogold compounds are promising anticancer drugs for AQP3‐overexpressing cancer therapeutic.