Editors' ChoiceCell Biology

Acid-addicted cells

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Science Signaling  01 Dec 2020:
Vol. 13, Issue 660, eabf8517
DOI: 10.1126/scisignal.abf8517

PRL3 enables cells to tolerate acidic pH and promotes metastasis by stimulating TRPML-dependent lysosome exocytosis.

One of the microenvironmental changes associated with cancer is acidification. Although acidosis is toxic to most normal cells, tumor cells adapt to and even thrive in low pH conditions, and acidic pH promotes cancer progression (see commentary by Hongu and Oskarsson). Funato et al. found that MDCK cells overexpressing phosphatase of regenerating liver 3 (PRL3), which promotes cancer progression and metastasis by binding to and inhibiting the Mg2+ transporter cyclin M (CNNM), not only proliferated faster than control cells under acidic conditions (pH 6.5 or 7.0), but also were unable to grow under normal physiological or basic conditions (pH 7.5 and above). These acid-addicted cells maintained a higher intracellular pH than did control cells under low, normal, and high pH conditions and had an unusually high amount of lysosomal exocytosis. Interfering with lysosomal exocytosis reversed the acid-addiction phenotype, consistent with the cells coping with acidosis by expelling H+. Intracellular Mg2+ accumulation promotes the production of reactive oxygen species (ROS), which can stimulate the lysosome-localized cation channel TRPML. The increased lysosomal exocytosis in PRL3-overexpressing cells was associated with increased intracellular Ca2+ and required both ROS and TRPMLs, and knocking out CNNM2 and CNNM4 stimulated lysosome exocytosis in HEK293 cells. TRPML1 knockout reversed PRL3-induced lysosome exocytosis in cultured mouse melanoma cells and prevented PRL3-dependent metastasis of these cells in vivo. Removal of the single PRL homolog in Caenorhabditis elegans or knocking down its TRPML homolog blocked lysosomal trafficking to the plasma membrane, whereas CNNM deletion promoted lysosome translocation to the plasma membrane. These findings are consistent with PRL3 promoting acid tolerance by stimulating TRPML-dependent lysosome exocytosis to raise intracellular pH.

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