Research Mentor Name
Dr. Wanlu Du
Research Mentor Email Address
wanludu@umich.edu
Institution / Department
University of Michigan - Ann Arbor / Department of Molecular, Cellular, and Developmental Biology
Document Type
Research Abstract
Research Type
basicbio
Level of Research
no
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 metastatic melanoma cells prevents such cell death, overexpression of TRPML1 in normal cells confers ML-SA vulnerability. In the melanoma mouse models, ML-SAs exhibit potent in vivo efficacy of suppressing tumor progression. Hence, targeting maladaptively upregulated lysosome machinery can selectively eradicate metastatic tumor cells in vitro and in vivo.
Disciplines
Medical Biochemistry | Medical Cell Biology | Medical Molecular Biology | Medical Pharmacology | Medical Physiology | Medicine and Health Sciences | Neoplasms
Recommended Citation
Du, Wanlu; Gu, Mingxue; Hu, Meiqin; Nold, Timothy; Pinchi, Prateeksunder; Chen, Wei; Ryan, Michael; Bannaga, Ahmed; and Xu, Haoxing, "Lysosomal Zn 2+ release triggers rapid, mitochondria-mediated, non-apoptotic cell death in metastatic melanoma" (2022). Medical Student Research Symposium. 177.
https://digitalcommons.wayne.edu/som_srs/177
Included in
Medical Biochemistry Commons, Medical Cell Biology Commons, Medical Molecular Biology Commons, Medical Pharmacology Commons, Medical Physiology Commons, Neoplasms Commons