Lysosomal Zn²⁺ release triggers rapid, mitochondria-mediated, non-apoptotic cell death in metastatic melanoma.

ABSTRACT: During tumor progression, lysosome function is often maladaptively upregulated to match the high energy demand required for cancer cell hyper-proliferation and invasion. Here, we report that mucolipin TRP channel 1 (TRPML1), a lysosomal Ca²⁺ and Zn²⁺ release channel that regulates multiple aspects of lysosome function, is dramatically upregulated in metastatic melanoma cells compared with normal cells. TRPML-specific synthetic agonists (ML-SAs) are sufficient to induce rapid (within hours) lysosomal Zn²⁺-dependent necrotic cell death in metastatic melanoma cells while completely sparing normal cells. ML-SA-caused mitochondria swelling and dysfunction lead to cellular ATP depletion. While pharmacological inhibition or genetic silencing of TRPML1 in metastati

SUBMITTER: Du W 

PROVIDER: S-EPMC8559338 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature