A unified approach to targeting the lysosome’s degradative and growth signaling roles
Document Type
Article
Publication Date
11-1-2017
Abstract
Lysosomes serve dual roles in cancer metabolism, executing catabolic programs (i.e., autophagy and macropinocytosis) while promoting mTORC1-dependent anabolism. Antimalarial compounds such as chloroquine or quinacrine have been used as lysosomal inhibitors, but fail to inhibit mTOR signaling. Further, the molecular target of these agents has not been identified. We report a screen of novel dimeric antimalarials that identifies dimeric quinacrines (DQ) as potent anticancer compounds, which concurrently inhibit mTOR and autophagy. Central nitrogen methylation of the DQ linker enhances lysosomal localization and potency. An in situ photoaffin-ity pulldown identified palmitoyl-protein thioesterase 1 (PPT1) as the molecular target of DQ661. PPT1 inhibition concurrently impairs mTOR and lysosomal catabolism through the rapid accumulation of palmitoylated proteins. DQ661 inhibits the in vivo tumor growth of melanoma, pancreatic cancer, and colorectal cancer mouse models and can be safely combined with chemotherapy. Thus, lysosome-directed PPT1 inhibitors represent a new approach to concurrently targeting mTORC1 and lysosomal catabolism in cancer. SIGNIFICANCE: This study identifies chemical features of dimeric compounds that increase their lysosomal specificity, and a new molecular target for these compounds, reclassifying these compounds as targeted therapies. Targeting PPT1 blocks mTOR signaling in a manner distinct from catalytic inhibitors, while concurrently inhibiting autophagy, thereby providing a new strategy for cancer therapy.
Identifier
85032959641 (Scopus)
Publication Title
Cancer Discovery
External Full Text Location
https://doi.org/10.1158/2159-8290.CD-17-0741
e-ISSN
21598290
ISSN
21598274
PubMed ID
28899863
First Page
1266
Last Page
1283
Issue
11
Volume
7
Grant
1R01CA198015
Fund Ref
National Institutes of Health
Recommended Citation
Rebecca, Vito W.; Nicastri, Michael C.; McLaughlin, Noel; Fennelly, Colin; McAfee, Quentin; Ronghe, Amruta; Nofal, Michel; Lim, Chun Yan; Witze, Eric; Chude, Cynthia I.; Zhang, Gao; Alicea, Gretchen M.; Piao, Shengfu; Murugan, Sengottuvelan; Ojha, Rani; Levi, Samuel M.; Wei, Zhi; Barber-Rotenberg, Julie S.; and Murphy, Maureen E., "A unified approach to targeting the lysosome’s degradative and growth signaling roles" (2017). Faculty Publications. 9233.
https://digitalcommons.njit.edu/fac_pubs/9233
