TRPML3 enhances drug resistance in non-small cell lung cancer cells by promoting Ca2+-mediated lysosomal trafficking

Lysosomes are emerging as versatile signaling hubs that mediate numerous cellular processes, including the development of drug resistance in cancer cells. Transient receptor potential mucolipin 3 (TRPML3), an endolysosomal Ca2+-permeable channel, is implicated in regulating lysosomal trafficking during endocytosis and autophagy. However, the role of TRPML3 in cancer progression remains unclear. In this study, we focused on identifying key molecules that modulate exosomal release triggered by lysosomal exocytosis during the development of gefitinib resistance in non-small cell lung cancer (NSCLC). We found that the basal release of exosomes and lysosomal exocytosis is higher in the gefitinib-resistant NSCLC cell line HCC827/GR than in the gefitinib-sensitive NSCLC cell line HCC827. Notably, exosomal release and lysosomal exocytosis were associated with an increase in TRPML3 expression. Lysosomal Ca2+ release via TRPML3 was triggered by the gefitinib-mediated elevation of lysosomal pH. Further-more, TRPML3 deficiency enhanced the gefitinib-mediated increase in sub-G0 cell population, reduction of cell proliferation, and poly (ADP-ribose) polymerase cleavage. These data demonstrated that TRPML3 is a promising modulator of drug resistance. By sensing the elevation of lysosomal pH, it mediates lysosomal Ca2+ release, lysosomal trafficking and exocytosis, and exosomal release. Taken together, our study is the first to report the autonomous defense mechanism developed in NSCLC cells against the small-molecule tyrosine kinase inhibitor gefitinib, leading to acquired drug resistance. (c) 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).

Automated summary

This study reveals the role of TRPML3 in regulating lysosomal exocytosis and exosomal release in the development of drug resistance in non-small cell lung cancer (NSCLC).