Aspartate is an endogenous metabolic limitation for tumour growth
Name
nihms969303.pdf
Description
Accepted version
Size
801.23 KB
Format
Adobe PDF
Checksum (MD5)
ea197d304d0bd2c62783111fc9b4e991
Author(s)
Sullivan, Lucas B.
Luengo, Alba
Danai, Laura V.
Bush, Lauren N.
Diehl, Frances F.
Hosios, Aaron M.
Lau, Allison N.
Elmiligy, Sarah
Lewis, Caroline A.
Vander Heiden, Matthew G.
Date Issued
June 25, 2018
Journal
Nature cell biology
Publisher
Springer Science and Business Media LLC
Citation
Sullivan, Lucas B. et al. “Aspartate is an endogenous metabolic limitatio for tumour growth.” Nature cell biology 20 (2018): 782-788 © 2018 The Author(s)
Version
Author's final manuscript
Abstract
Defining the metabolic limitations of tumour growth will help to develop cancer therapies 1 . Cancer cells proliferate slower in tumours than in standard culture conditions, indicating that a metabolic limitation may restrict cell proliferation in vivo. Aspartate synthesis can limit cancer cell proliferation when respiration is impaired 2-4 ; however, whether acquiring aspartate is endogenously limiting for tumour growth is unknown. We confirm that aspartate has poor cell permeability, which prevents environmental acquisition, whereas the related amino acid asparagine is available to cells in tumours, but cancer cells lack asparaginase activity to convert asparagine to aspartate. Heterologous expression of guinea pig asparaginase 1 (gpASNase1), an enzyme that produces aspartate from asparagine 5 , confers the ability to use asparagine to supply intracellular aspartate to cancer cells in vivo. Tumours expressing gpASNase1 grow at a faster rate, indicating that aspartate acquisition is an endogenous metabolic limitation for the growth of some tumours. Tumours expressing gpASNase1 are also refractory to the growth suppressive effects of metformin, suggesting that metformin inhibits tumour growth by depleting aspartate. These findings suggest that therapeutic aspartate suppression could be effective to treat cancer.
Subjects
Cell Biology
MIT Department
Whitehead Institute for Biomedical Research
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1038/s41556-018-0125-0
