@article {Sironimol.118.113118, author = {Juan Sironi and Evelyn Aranda and Lars Ulrik Nordstrom and Edward L Schwartz}, title = {Lysosome membrane permeabilization and disruption of mTOR-lysosome interaction are associated with the inhibition of lung cancer cell proliferation by a chloroquinoline analog}, elocation-id = {mol.118.113118}, year = {2018}, doi = {10.1124/mol.118.113118}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Lysosomes degrade cellular proteins and organelles, and regulate cell signaling by providing a surface for the formation of critical protein complexes, notably mTORC1. The striking differences in the lysosomes of cancer versus normal cells suggest that the lysosome would be a target for drug development. While the lysomotropic drugs chloroquine (CQ) and hydroxychloroquine (HCQ) have been widely investigated, studies have focused on their ability to inhibit autophagy. We synthesized a novel compound, named EAD1, that is structurally related to CQ but is 14-fold more potent. Here we find that EAD1 causes rapid lysosome relocation, lysosome membrane permeabilization (LMP), and lysosome deacidification, induces apoptosis, and irreversibly blocks lung cancer cell proliferation. EAD1 also potently causes the dissociation of mTOR from lysosomes and increases mTOR{\textquoteright}s perinuclear vs cytoplasmic localization, changes previously shown to inactivate mTORC1. The effect on mTOR was not seen with HCQ, even at \>10-fold higher concentrations. Phosphorylation of a downstream target of mTORC1, ribosomal protein S6, was inhibited by EAD1. Although EAD1 also inhibited autophagy, it strikingly retained full antiproliferative activity in autophagy-deficient H1650 lung cancer cells, which have a biallelic deletion within the Atg7 locus, and in H460 Atg7-knockout cells. As Atg7 is critical for the canonical autophagy pathway, it is likely that inhibition of autophagy is not how EAD1 inhibits cell proliferation. Further studies are needed to determine the relationship of LMP to mTORC1 disruption, and their relative contributions to drug-induced cell death. These studies support the lysosome as an underexplored target for new drug development.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/early/2018/11/08/mol.118.113118}, eprint = {https://molpharm.aspetjournals.org/content/early/2018/11/08/mol.118.113118.full.pdf}, journal = {Molecular Pharmacology} }