Migration at the Gate: The role of Lysosomal Calcium Channel TRPML-1 in Endolysosomal Regulation and Cancer Cell Invasion.

Abstract

Correlation between lysosomes and cancer has been demonstrated in many studies. Lysosomal compartments in cancer showed various differences compared to normal conditions, such as their activity, biogenesis, hydrolytic activity and exocytosis. The lysosome itself contains many ionic channels on its membrane which regulate lysosomal activity and functionality, among which TRPML-1, a calcium releasing channel, was shown to play an important role in cancer invasion. In this study we investigated the role TRPML-1 has in lysosomal regulation and in HT1080 cancer invasion specifically. Overexpression of these channels in HT1080 cells caused the creation of enlarged endolysosomal compartments possessing the same acidic range as normal lysosomes, and containing active cathepsin and calcium ions in their intraluminal environments. On the other hand, depletion of TRPML-1 caused slightly smaller and more lysosomal organelles to appear in HT1080 cells. We also showed TRPML-1 alteration not merely alters lysosomal organelles, but also affects other organelles within the cell, with regard to their interaction and distribution. We showed increased association of ER and mitochondria upon TRPML-1 depletion and the appearance of lipid droplets in these cells. We also showed TRPML-1 knockdown increased the level of lysosomal proteins and translocated transcription factor E3 to the nucleus. In line with the link between this channel and invasive cancer we showed that TRPML-1 upregulation significantly increases lysosomal exocytosis, which in turn increases ECM degradation and cell migration.