Endolysosomal TRPML1 channel regulates cancer cell migration by altering intracellular trafficking of E-cadherin and β ₁-integrin

Abstract

Metastasis still accounts for 90% of all cancer-related death cases. An increase of cellular mobility and invasive traits of cancer cells mark two crucial prerequisites of metastasis. Recent studies highlight the involvement of the endolysosomal cation channel TRPML1 in cell migration. Our results identified a widely antimigratory effect upon loss of TRPML1 function in a panel of cell lines in vitro and reduced dissemination in vivo. As mode-of-action, we established TRPML1 as a crucial regulator of cytosolic calcium levels, actin polymerization, and intracellular trafficking of two promigratory proteins: E-cadherin and β ₁-integrin. Interestingly, KO of TRPML1 differentially interferes with the recycling process of E-cadherin and β ₁-integrin in a cell line–dependant manner, while resulting in the same phenotype of decreased migratory and adhesive capacities in vitro. Additionally, we observed a coherence between reduction of E-cadherin levels at membrane site and phosphorylation of NF-κB in a β-catenin/p38-mediated manner. As a result, an E-cadherin/NF-κB feedback loop is generated, regulating E-cadherin expression on a transcriptional level. Consequently, our findings highlight the role of TRPML1 as a regulator in migratory processes and suggest the ion channel as a suitable target for the inhibition of migration and invasion.