Sex inequalities in cancer are well documented, but the current limited understanding is hindering advances in precision medicine and therapies1. Consideration of ethnicity, age and sex is essential for the management of cancer patients because they underlie important differences in both incidence and response to treatment2,3. Age-related hormone production, which is a consistent divergence between the sexes, is underestimated in cancers that are not recognized as being hormone dependent4-6. Here, we show that premenopausal women have increased vulnerability to cancers, and we identify the cell-cell adhesion molecule E-cadherin as a crucial component in the oestrogen response in various cancers, including melanoma. In a mouse model of melanoma, we discovered an oestrogen-sensitizing pathway connecting E-cadherin, β-catenin, oestrogen receptor-α and GRPR that promotes melanoma aggressiveness in women. Inhibiting this pathway by targeting GRPR or oestrogen receptor-α reduces metastasis in mice, indicating its therapeutic potential. Our study introduces a concept linking hormone sensitivity and tumour phenotype in which hormones affect cell phenotype and aggressiveness. We have identified an integrated pro-tumour pathway in women and propose that targeting a G-protein-coupled receptor with drugs not commonly used for cancer treatment could be more effective in treating E-cadherin-dependent cancers in women. This study emphasizes the importance of sex-specific factors in cancer management and offers hope of improving outcomes in various cancers.
© 2025. The Author(s).

G protein-coupled receptors (GPCRs) can temporally alter signaling by generating secondary signals from internalized receptors. However, the motifs required to direct GPCRs to these pathways are ill defined. The GPCR, calcium-sensing receptor (CaSR), regulates parathyroid hormone release by promiscuous G protein coupling at cell surfaces and by selectively recruiting Gq/11 to early endosomal membranes. Here, we demonstrate that a dileucine endocytic motif is required for directing CaSR to dynamic spatiotemporal pathways by interacting with the adaptor protein-2 σ-subunit, which is mutated in hypercalcemic patients. From early endosomes, internalized CaSR is targeted to spatially distinct pathways involving early-to-recycling and late endosomes, to direct compartment-specific signals and regulate GPCR forward trafficking. The clinically available allosteric modulator cinacalcet biases signaling to preferentially enhance early endosomal-to-recycling pathways, demonstrating the veracity of targeting discrete endosomal pathways. These results reveal that single GPCRs can simultaneously activate spatially distinct endosomal pathways and demonstrate the structural motifs that facilitate such multidimensional signaling.
© 2025 The Authors.

In mammals, the calcium-sensing receptor (CaSR) is involved in nutrient sensing and modulated by several amino acids. In teleosts, sequence homologues of the mammalian CaSR have been described but their function in sensing amino acids remains elusive, including in Atlantic salmon (Salmo salar), an important aquaculture species. This study investigated the activation of Atlantic salmon Casr (asCasr)-mediated signaling pathways-Gq, Gi, and ERK1/2-by six selected L-amino acids (histidine, tryptophan, phenylalanine, isoleucine, leucine and valine) and by Ca2+. Using a Flp-In-HEK293 cell line stably expressing asCasr, we confirmed activation of all three pathways. L-histidine, L-phenylalanine, and L-tryptophan triggered Gi signaling independent of Ca²⁺. Notably, no Ca²⁺ concentrations induced Gi activation, but IP1 production increased in a concentration-dependent manner. L-histidine was the only amino acid to activate the Gq pathway without Ca²⁺, and this response was amplified by the presence of Ca²⁺. In the presence of 2.5 mM Ca²⁺, L-phenylalanine and L-tryptophan also activated Gq signaling in a concentration-dependent manner. Additionally, in the presence of 10 mM Ca²⁺, L-histidine, L-phenylalanine, and L-tryptophan triggered ERK phosphorylation. These findings establish asCasr as a functional homologue of mammalian CaSR, activated in a concentration-dependent manner by L-amino acids with an aromatic ring.
© 2025. The Author(s).

The intricate link between glucose metabolism, ATP production, and glucose-stimulated insulin secretion (GIIS) in pancreatic β-cells has been well established. However, the effects of other digestible monosaccharides on this mechanism remain unclear. This study examined the interaction between intracellular fructose metabolism and GIIS using MIN6-K8 β-cell lines and mouse pancreatic islets. Fructose at millimolar concentrations potentiated insulin secretion in the presence of stimulatory levels (8.8 mM) of glucose. This potentiation was dependent on sweet taste receptor-activated phospholipase Cβ2 (PLCβ2) signaling. Concurrently, metabolic tracing using 13C-labeled fructose and glucose in conjunction with biochemical analyses demonstrated that fructose blunted the glucose-induced increase in the ATP/ADP ratio. Mechanistically, fructose is substantially converted to fructose 1-phosphate (F1P) at the expense of ATP. F1P directly inhibited PKM2 (pyruvate kinase M2), thereby reducing the later glycolytic flux used for ATP production. Remarkably, F1P-mediated PKM2 inhibition was counteracted by TEPP-46, a small-molecule PKM2 activator. TEPP-46 restored glycolytic flux and the ATP/ADP ratio, leading to the enhancement of fructose-potentiated GIIS in MIN6-K8 cells, normal mouse islets, and fructose-unresponsive diabetic mouse islets. These findings reveal an antagonistic interplay between glucose and fructose metabolism in β-cells, highlighting PKM2 as a crucial regulator and broadening our understanding of the relationship between β-cell fuel metabolism and insulin secretion.
© 2025 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.

β-adrenergic blockers (β-blockers) are extensively used to inhibit β-adrenoceptor activation and subsequent cAMP production in many cell types. In this study, we characterized the effects of β-blockers on mouse pancreatic β-cells. Unexpectedly, high concentrations (100 μM) of β-blockers (propranolol and bisoprolol) paradoxically increased cAMP levels 5-10 fold, enhanced Ca2+ influx, and stimulated a 2-4 fold increase in glucose- and glimepiride-induced insulin secretion in MIN6-K8 clonal β-cells and isolated mouse pancreatic islets. These effects were observed despite minimal expression of β-adrenoceptors in these cells. Mechanistically, the cAMP increase led to ryanodine receptor 2 (RYR2) phosphorylation via protein kinase A (PKA), triggering Ca2+-induced Ca2+ release (CICR). CICR then activates transient receptor potential cation channel subfamily M member 5 (TRPM5), resulting in increased Ca2+ influx via voltage-dependent Ca2+ channels. These effects contradict the conventional understanding of the pharmacology of β-blockers, highlighting the variability in β-blocker actions depending on the experimental context.
© 2025 The Author(s). Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.