The DOI matches its Crossref record; 14 of the 14 references it cites were found in a registry or an index.
A Unified Approach to Targeting the Lysosome's Degradative and Growth Signaling Roles
Open accessAbstract
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 photoaffinity 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. Cancer Discov; 7(11); 1266–83. ©2017 AACR. See related commentary by Towers and Thorburn, p. 1218. This article is highlighted in the In This Issue feature, p. 1201
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Cites
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Self-citationRadiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer
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Self-citationTranscriptional control of autophagy-lysosome function drives pancreatic cancer metabolism
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Cited by
Targeting Autophagy in Cancer: Recent Advances and Future Directions
Amaravadi, R. K., Kimmelman, A. C., & Debnath, J. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-0292 · Cited by 928
Self-citationThe lysosome as a cellular centre for signalling, metabolism and quality control
Lawrence, R. E., & Zoncu, R. (2019) · Nature Cell Biology · doi:10.1038/s41556-018-0244-7 · Cited by 920
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Self-citationAutophagy in tumour immunity and therapy
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Autophagy, cancer stem cells and drug resistance
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Metadata
- Authors
- Rebecca, V. W., Nicastri, M. C., McLaughlin, N., Fennelly, C., McAfee, Q., Ronghe, A., Nofal, M., Lim, C.-Y., Witze, E., Chude, C. I., Zhang, G., Alicea, G. M., Piao, S., Murugan, S., Ojha, R., Levi, S. M., Wei, Z., Barber-Rotenberg, J. S., Murphy, M. E., Mills, G. B., Lu, Y., Rabinowitz, J., Marmorstein, R., Liu, Q., Liu, S., Xu, X., Herlyn, M., Zoncu, R., Brady, D. C., Speicher, D. W., Winkler, J. D., & Amaravadi, R. K.
- Venue
- Cancer Discovery
- Published
- 2017-11-01
- Volume
- 7
- Issue
- 11
- Pages
- 1266-1283
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- OpenAlex
- W2755560018
- Cited by
- 209
- References
- 14
- FWCI
- 14.65
- Type
- journal article
- Language
- en
- Open access
- green
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- Rebecca, V. W., Nicastri, M. C., McLaughlin, N., Fennelly, C., McAfee, Q., Ronghe, A., Nofal, M., Lim, C.-Y., Witze, E., Chude, C. I., Zhang, G., Alicea, G. M., Piao, S., Murugan, S., Ojha, R., Levi, S. M., Wei, Z., Barber-Rotenberg, J. S., Murphy, M. E., . . . Amaravadi, R. K. (2017). A Unified Approach to Targeting the Lysosome's Degradative and Growth Signaling Roles. Cancer Discovery. https://doi.org/10.1158/2159-8290.cd-17-0741
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