Host: The Japanese Society of Toxicology
Name : The 51st Annual Meeting of the Japanese Society of Toxicology
Date : July 03, 2024 - July 05, 2024
PRL is highly expressed in malignant cancer tissues, such as metastases of colorectal cancers. We found an evolutionarily conserved magnesium ion efflux transporter, CNNM, as a direct binding molecule of PRL. PRL inhibits the transporter function of CNNM and increases intracellular magnesium levels. Through analyses using CNNM gene-deficient mice and cultured cancer cells, we also found that intracellular magnesium accumulation due to inhibition of CNNM function alters cellular functions and causes malignant progression of cancer. In cells expressing high levels of PRL, ATP levels increased along with magnesium levels, and lysosomal exocytosis, in which lysosomes fuse with the plasma membrane and expel protons and other substances accumulated in the lumen, was found to be activated. Malignant cancer tissues are known to be acidic, and the active proton efflux allowed them to grow actively in an acidic environment. Deletion of CNNM in the nematode C. elegans resulted in a shorter lifespan, which was attributed to an increase in reactive oxygen species (ROS) in the intestinal cells, in conjunction with an increase in magnesium and ATP. We found that such ROS production also occurs in mammalian cells and is important for lysosomal exocytosis. In this symposium, we will introduce the intracellular magnesium regulation and ROS production, which was revealed by the studies on PRL/CNNM, and its role in the progression of cancer malignancy.
