The Oncogenic PRL Protein Causes Acid Addiction of Cells by Stimulating Lysosomal Exocytosis(from Miki Lab, in Dev. Cell)

Extracellular pH is usually maintained around 7.4 in multicellular organisms, and cells are optimized to proliferate under this condition. Yosuke Funato, Hiroaki Miki (Department of Cellular Regulation, RIMD, Osaka university) and their research group 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 alignancy.


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.



This article is published in Developmental Cell, in Sep 12, 2020.

Title: “The oncogenic PRL protein causes acid addiction of cells by stimulating lysosomal exocytosis

Authors: Yosuke Funato, Atsushi Yoshida, Yusuke Hirata, Osamu Hashizume, Daisuke Yamazaki, and Hiroaki Miki

  • Model of lysosomal exocytosis and acid addiction by PRL