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N-myristoyltransferase-1 is necessary for lysosomal degradation and mTORC1 activation in cancer cells

Chen, Yu-Chuan and Navarrete, Marian S. and Wang, Ying and McClintock, Natalie C. and Sakurai, Reiko and Wang, Feng and Chen, Kathryn T. and Chou, Tsui-Fen and Rehan, Virender K. and Lee, Delphine J. and Diaz, Begoña (2020) N-myristoyltransferase-1 is necessary for lysosomal degradation and mTORC1 activation in cancer cells. Scientific Reports, 10 . Art. No. 11952. ISSN 2045-2322. https://resolver.caltech.edu/CaltechAUTHORS:20200727-084934912

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Abstract

N-myristoyltransferase-1 (NMT1) catalyzes protein myristoylation, a lipid modification that is elevated in cancer cells. NMT1 sustains proliferation and/or survival of cancer cells through mechanisms that are not completely understood. We used genetic and pharmacological inhibition of NMT1 to further dissect the role of this enzyme in cancer, and found an unexpected essential role for NMT1 at promoting lysosomal metabolic functions. Lysosomes mediate enzymatic degradation of vesicle cargo, and also serve as functional platforms for mTORC1 activation. We show that NMT1 is required for both lysosomal functions in cancer cells. Inhibition of NMT1 impaired lysosomal degradation leading to autophagy flux blockade, and simultaneously caused the dissociation of mTOR from the surface of lysosomes leading to decreased mTORC1 activation. The regulation of lysosomal metabolic functions by NMT1 was largely mediated through the lysosomal adaptor LAMTOR1. Accordingly, genetic targeting of LAMTOR1 recapitulated most of the lysosomal defects of targeting NMT1, including defective lysosomal degradation. Pharmacological inhibition of NMT1 reduced tumor growth, and tumors from treated animals had increased apoptosis and displayed markers of lysosomal dysfunction. Our findings suggest that compounds targeting NMT1 may have therapeutic benefit in cancer by preventing mTORC1 activation and simultaneously blocking lysosomal degradation, leading to cancer cell death.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1038/s41598-020-68615-wDOIArticle
ORCID:
AuthorORCID
Diaz, Begoña0000-0002-7892-6319
Additional Information:© The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Received 28 March 2020; Accepted 25 June 2020; Published 20 July 2020. Data availability: Materials and data generated during the current study are available from the corresponding author on reasonable request. We thank Dr. Shawn Ferguson for sharing the TFE3-GFP plasmid. We thank Isabel Mejia for help with TFE3-GFP DNA purification, Mishal I. Syed for help with colony assays in Supplementary Figures, and Stacy Behare for technical assistance with animal experiments. We thank Guillermina Garcia at the Sanford-Burnham Prebys Medical Discovery Institute Histopathology Service (La Jolla), and Catalina Guerra and Jenny Dancourt at the Lundquist Institute Bioresources Center for valuable technical support. We are thankful to Dr. Samuel W. French (Harbor-UCLA Medical Center) for expert histopathological evaluation of H&E stained mouse organs. We are grateful to Dr. Sara Courtneidge (OHSU) and Dr. David Shackelford (UCLA) for useful critical comments on the manuscript. This work has been supported by grants NIH HL127237 and TRDRP 27IP-0050 to VKR, and The Lundquist Institute Grant to BD. Author Contributions: Y.C. performed and analyzed WB, proliferation, colony assays, IF, and animal experiments; M.N. performed and analyzed IHC on tumor sections and quantified IF experiments; Y.W. designed, performed and interpreted animal experiments; N.M. assisted with animal experiments; R.S. assisted with animal experiments and performed WB of tumors; F.W. designed, performed and interpreted NMTi viability experiments to calculate EC₅₀; K.T.C. performed and interpreted animal experiments; T.C. designed and interpreted NMTi viability experiments to calculate EC₅₀; V.K.R. designed and interpreted animal experiments; D.J.L. designed and interpreted IHC experiments; B.D. conceived the project, designed and performed experiments, coordinated and supervised the project, analyzed and interpreted data, and wrote the manuscript. All authors read and approved the manuscript. The authors declare no competing interests.
Funders:
Funding AgencyGrant Number
NIHHL127237
California Tobacco-Related Disease Research Program27IP-0050
Lundquist InstituteUNSPECIFIED
Subject Keywords:Cancer; Cell biology
Record Number:CaltechAUTHORS:20200727-084934912
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200727-084934912
Official Citation:Chen, Y., Navarrete, M.S., Wang, Y. et al. N-myristoyltransferase-1 is necessary for lysosomal degradation and mTORC1 activation in cancer cells. Sci Rep 10, 11952 (2020). https://doi.org/10.1038/s41598-020-68615-w
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:104581
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:28 Jul 2020 20:14
Last Modified:28 Jul 2020 20:14

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