The Oncogenic PRL Protein Causes Acid Addiction of Cells by Stimulating Lysosomal Exocytosis
| Autor: | Atsushi Yoshida, Yosuke Funato, Daisuke Yamazaki, Hiroaki Miki, Osamu Hashizume, Yusuke Hirata |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
TRPML
Phosphatase General Biochemistry Genetics and Molecular Biology Exocytosis Metastasis Immediate-Early Proteins Madin Darby Canine Kidney Cells Evolution Molecular 03 medical and health sciences 0302 clinical medicine Dogs medicine Extracellular Animals Humans Neoplasm Metastasis Caenorhabditis elegans Molecular Biology Conserved Sequence 030304 developmental biology 0303 health sciences Tumor microenvironment biology Cancer Cell Biology Intracellular Membranes medicine.disease biology.organism_classification Cell biology Neoplasm Proteins Mice Inbred C57BL HEK293 Cells Cancer cell CRISPR-Cas Systems Protein Tyrosine Phosphatases Lysosomes Acids 030217 neurology & neurosurgery Developmental Biology |
| Zdroj: | Developmental cell. 55(4) |
| ISSN: | 1878-1551 |
| Popis: | Extracellular pH is usually maintained around 7.4 in multicellular organisms, and cells are optimized to proliferate under this condition. Here, we find cells can adapt to a more acidic pH of 6.5 and become addicted to this acidic microenvironment by expressing phosphatase of regenerating liver (PRL), a driver of cancer malignancy. Genome-scale CRISPR-Cas9 knockout screening and subsequent analyses revealed that PRL promotes H+ extrusion and acid addiction by stimulating lysosomal exocytosis. Further experiments using cultured cells and Caenorhabditis elegans clarified the molecular link between PRL and lysosomal exocytosis across species, involving activation of lysosomal Ca2+ channel TRPML by ROS. Indeed, disruption of TRPML in cancer cells abolished PRL-stimulated lysosomal exocytosis, acid addiction, and metastasis. Thus, PRL is the molecular switch turning cells addicted to an acidic condition, which should benefit cancer cells to thrive in an acidic tumor microenvironment. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|