Activation of TRPV4 Induces Exocytosis and Ferroptosis in Human Melanoma Cells

Abstract

TRPV4 (transient receptor potential vanilloid 4), a calcium permeable TRP ion channel, is known to play a key role in endocytosis. However, whether it contributes to exocytosis remains unclear. Here, we report that activation of TRPV4 induced massive exocytosis in both melanoma A375 cell and heterologous expression systems. We show here that, upon application of TRPV4-specific agonists, prominent vesicle priming from endoplasmic reticulum (ER) was observed, followed by morphological changes of mitochondrial crista may lead to cell ferroptosis. We further identified interactions between TRPV4 and folding/vesicle trafficking proteins, which were triggered by calcium entry through activated TRPV4. This interplay, in turn, enhanced TRPV4-mediated activation of folding and vesicle trafficking proteins to promote exocytosis. Our study revealed a signaling mechanism underlying stimulus-triggered exocytosis in melanoma and highlighted the role of cellular sensor TRPV4 ion channel in mediating ferroptosis.

Role of TRPV1 ion channel in cervical squamous cell carcinoma genesis

“…As upstream signaling regulators of cell death, TRPM channels have been involved in-relevant pathologies ( Shi et al, 2021 ). Activation of TRPV4 induces exocytosis and ferroptosis in human melanoma cells ( Li et al, 2022 ).…”

Pan-Cancer Analysis of the TRP Family, Especially TRPV4 and TRPC4, and Its Expression Correlated with Prognosis, Tumor Microenvironment, and Treatment Sensitivity

“…Li M et al reported that the stimulation of native TRPV4 or transiently transfected TRPV4 in A375 cells (human melanoma cell line) could induce significant extracellular secretion, which acquired TRPV4-mediated calcium influx, as well as a series of key regulators of exocytosis including lysosome-associated proteins and multiple folding and vesicular transporters. By identifying a series of intracellular events after TRPV4 activation, Li M et al demonstrated a critical role of TRPV4 in extracellular processes and calcium-mediated ferroptosis [36]. Additionally, administration of 4α-PDD (agonist of TRPV4) downregulated adhesion−related tumor suppressor genes in 4T07 (mouse breast cancer cell line).…”

TRPM2 Mediates Hepatic Ischemia–Reperfusion Injury via Ca 2+ -Induced Mitochondrial Lipid Peroxidation through Increasing ALOX12 Expression

“…To date, 3 pathways, including GPX4 and iron and lipid metabolites, are required for ferroptosis [ 63 ]. Interestingly, mounting evidence suggests that calcium overload may be involved in ferroptosis, and a recent study reported that the calcium-permeable channel, TRPV4, was upregulated during ferroptosis [ 65 ]; however, the underlying mechanism is unknown. In our study, RNA sequencing analysis revealed that differentially expressed genes associated with TRPM2-induced hepatic IR injury were clustered in key pathways of ferroptosis, such as the oxidation reduction and GSH metabolic processes.…”