Reactive oxygen species (ROS), including H₂O₂, contribute to oxidative stress and may cause cancer initiation and progression. However, at low concentrations, H₂O₂ can regulate signaling pathways modulating cell growth, differentiation, and migration. A few mammalian aquaporins (AQPs) facilitate H₂O₂ diffusion across membranes and participate in tumorigenesis. AQP3 and AQP5 are strongly expressed in cancer tissues and AQP3-mediated H₂O₂ transport has been related to breast cancer cell migration, but studies with human AQP5 are lacking. Here, we report that, in addition to its established water permeation capacity, human AQP5 facilitates transmembrane H₂O₂ diffusion and modulates cell growth of AQP5-transformed yeast cells in response to oxidative stress. Mutagenesis studies revealed that residue His173 located in the selective filter is crucial for AQP5 permeability, and interactions with phosphorylated Ser183 may regulate permeation through pore blockage. Moreover, in human pancreatic cancer cells, the measured AQP5-mediated H₂O₂ influx rate indicates the presence of a highly efficient peroxiporin activity. Cell migration was similarly suppressed by AQP3 or AQP5 gene silencing and could be recovered by external oxidative stimuli. Altogether, these results unveiled a major role for AQP5 in dynamic fine-tuning of the intracellular H₂O₂ concentration, and consequently in activating signaling networks related to cell survival and cancer progression, highlighting AQP5 as a promising drug target for cancer therapies.

Polyoxometalates (POMs) are of increasing interest due to their proven anticancer activities. Aquaporins (AQPs) were found to be overexpressed in tumors bringing particular attention to their inhibitors as anticancer drugs. Herein, we report for the first time the ability of polyoxotungstates (POTs), such as of Wells–Dawson P₂W₁₈, P₂W₁₂, and P₂W₁₅, and Preyssler P₅W₃₀ structures, to affect aquaporin-3 (AQP3) activity and impair melanoma cell migration. The tested POTs were revealed to inhibit AQP3 function with different effects, with P₂W₁₈, P₂W₁₂, and P₅W₃₀ being the most potent (50% inhibitory concentration (IC₅₀) = 0.8, 2.8, and 3.2 µM), and P₂W₁₅ being the weakest (IC50 > 100 µM). The selectivity of P₂W₁₈ toward AQP3 was confirmed in yeast cells transformed with human aquaglyceroporins. The effect of P₂W₁₂ and P₂W₁₈ on melanoma cells that highly express AQP3 revealed an impairment of cell migration between 55% and 65% after 24 h, indicating that the anticancer properties of these compounds may in part be due to the blockage of AQP3-mediated permeability. Altogether, our data revealed that P₂W₁₈ strongly affects AQP3 activity and cancer cell growth, unveiling its potential as an anticancer drug against tumors where AQP3 is highly expressed.

Aquaporins (AQPs) are transmembrane proteins that facilitate the transport of water and small solutes, including glycerol, hydrogen peroxide and ions, across cell membranes. Beyond their established physiological roles in water regulation and metabolic processes, AQPs also exhibit receptor-like signaling activities in cancer-associated signaling pathways, integrating the dual roles of transporters and receptors, hence functioning as transceptors. This dual functionality underpins their critical involvement in cancer biology, where AQPs play key roles in promoting cell proliferation, migration, and invasion, contributing significantly to carcinogenesis. Among the AQPs, AQP1, AQP3 and AQP5 have been consistently identified as being aberrantly expressed in various tumor types. Their overexpression is strongly associated with tumor progression, metastasis, and poor patient prognosis. This review explores the pivotal roles of AQP1, AQP3 and AQP5 as transceptors in cancer biology, underscoring their importance as pharmacological targets. It highlights the urgent need for the development of effective modulators to target these AQPs, offering a promising avenue to enhance current therapeutic approaches for cancer treatment.

The natural polyphenolic compound Rottlerin (RoT) showed anticancer properties in a variety of human cancers through the inhibition of several target molecules implicated in tumorigenesis, revealing its potential as an anticancer agent. Aquaporins (AQPs) are found overexpressed in different types of cancers and have recently emerged as promising pharmacological targets. Increasing evidence suggests that the water/glycerol channel aquaporin-3 (AQP3) plays a key role in cancer and metastasis. Here, we report the ability of RoT to inhibit human AQP3 activity with an IC₅₀ in the micromolar range (22.8 ± 5.82 µM for water and 6.7 ± 2.97 µM for glycerol permeability inhibition). Moreover, we have used molecular docking and molecular dynamics simulations to understand the structural determinants of RoT that explain its ability to inhibit AQP3. Our results show that RoT blocks AQP3-glycerol permeation by establishing strong and stable interactions at the extracellular region of AQP3 pores interacting with residues essential for glycerol permeation. Altogether, our multidisciplinary approach unveiled RoT as an anticancer drug against tumors where AQP3 is highly expressed providing new information to aquaporin research that may boost future drug design.

The regulation of glycerol permeability in the gastrointestinal tract is crucial to control fat deposition, lipolysis and gluconeogenesis. Knowing that the amino acid glutamine is a physiological regulator of gluconeogenesis, whereas cystine promotes adiposity, herein we investigated the effects of dietary supplementation with glutamine and cystine on the serum biochemical parameters of piglets fed on amino acid-enriched diets, as well as on the transcriptional profile of membrane water and glycerol channels aquaporins (AQPs) in the ileum portion of the small intestine and its impact on intestinal permeability. Twenty male piglets with an initial body weight of 8.8 ± 0.89 kg were allocated to four dietary treatments (n = 5) and received, during a four week-period, a basal diet without supplementation (control) or supplemented with 8 kg/ton of glutamine (Gln), cystine (Cys) or the combination of the two amino acids in equal proportions (Gln + Cys). Most biochemical parameters were found improved in piglets fed Gln and Cys diet. mRNA levels of AQP3 were found predominant over the others. Both amino acids, individually or combined, were responsible for a consistent downregulation of AQP1, AQP7 and AQP10, without impacting on water permeability. Conversely, Cys enriched diet upregulated AQP3 enhancing basolateral membranes glycerol permeability and downregulating glycerol kinase (GK) of intestinal cells. Altogether, our data reveal that amino acids dietary supplementation can modulate intestinal AQPs expression and unveil AQP3 as a promising target for adipogenesis regulation.

The inhibition of glycerol permeation via human aquaporin-10 (hAQP10) by organometallic gold complexes has been studied by stopped-flow fluorescence spectroscopy, and its mechanism has been described using molecular modelling and atomistic simulations. The most effective hAQP10 inhibitors are cyclometalated Au(III) C^{^}N compounds known to efficiently react with cysteine residues leading to the formation of irreversible C–S bonds. Functional assays also demonstrate the irreversibility of the binding to hAQP10 by the organometallic complexes. The obtained computational results by metadynamics show that the local arylation of Cys209 in hAQP10 by one of the gold inhibitors is mapped into a global change of the overall free energy of glycerol translocation across the channel. Our study further pinpoints the need to understand the mechanism of glycerol and small molecule permeation as a combination of local structural motifs and global pore conformational changes, which are taking place on the scale of the translocation process and whose study, therefore, require sophisticated molecular dynamics strategies.