Feedback

Endolysosomal TRPML1 channel regulates cancer cell migration by altering intracellular trafficking of E-cadherin and β1-integrin.

ORCID
0009-0007-4648-3641
Affiliation
Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
Ouologuem, Lina;
Affiliation
Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
Frey, Nadine;
Affiliation
Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
Blenninger, Julia;
Affiliation
Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
Siow, Wei-Xiong;
Affiliation
Department of Pharmacy, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
Thorn-Seshold, Julia;
Affiliation
Gene Center, Laboratory for Functional Genome Analysis, Ludwig Maximilians-University Munich, 81377 Munich, Germany
Stöckl, Jan;
Affiliation
Walther-Straub-Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University Munich, 80336 Munich, Germany
Abrahamian, Carla;
Affiliation
Gene Center, Laboratory for Functional Genome Analysis, Ludwig Maximilians-University Munich, 81377 Munich, Germany
Fröhlich, Thomas;
Affiliation
Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
Vollmar, Angelika M.;
Affiliation
Walther-Straub-Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University Munich, 80336 Munich, Germany
Grimm, Christian;
Affiliation
Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
Bartel, Karin

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 anti-migratory 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 polymerisation and intracellular trafficking of two pro-migratory proteins: E-cadherin and β1-integrin. Interestingly, knockout (KO) of TRPML1 differentially interferes with the recycling process of E-cadherin and β1-integrin in a cell line dependant manner, whilst 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.

Cite

Citation style:
Could not load citation form.

Access Statistic

Total:
Downloads:
Abtractviews:
Last 12 Month:
Downloads:
Abtractviews:

Rights

Use and reproduction: