Abstract
Dietary restriction delays the incidence and decreases the growth of various types of tumours, but the mechanisms underlying the sensitivity of tumours to food restriction remain unknown. Here we show that certain human cancer cell lines, when grown as tumour xenografts in mice, are highly sensitive to the anti-growth effects of dietary restriction, whereas others are resistant. Cancer cells that form dietary-restriction-resistant tumours carry mutations that cause constitutive activation of the phosphatidylinositol-3-kinase (PI3K) pathway and in culture proliferate in the absence of insulin or insulin-like growth factor 1. Substitution of an activated mutant allele of PI3K with wild-type PI3K in otherwise isogenic cancer cells, or the restoration of PTEN expression in a PTEN-null cancer cell line, is sufficient to convert a dietary-restriction-resistant tumour into one that is dietary-restriction-sensitive. Dietary restriction does not affect a PTEN-null mouse model of prostate cancer, but it significantly decreases tumour burden in a mouse model of lung cancer lacking constitutive PI3K signalling. Thus, the PI3K pathway is an important determinant of the sensitivity of tumours to dietary restriction, and activating mutations in the pathway may influence the response of cancers to dietary restriction-mimetic therapies.
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30 April 2020
"An amendment to this paper has been published and can be accessed via a link at the top of the paper."
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Acknowledgements
We thank B. Vogelstein for providing the isogenic DLD-1 cell lines and M. M. Georgescu for the doxycycline-inducible U87-MG cell line; T. Jacks for the KRAS LA2; p53 LSL/WT mice and H. Wu for the Pb-Cre; PTEN L/L mice; F. Reinhardt for assistance with animal experiments; R. Bronson for histological analysis; the Histology Facility at the Koch Institute for Integrative Cancer Research and the Histology Core Laboratory at MIT for assistance with sectioning and immunohistochemistry; the Imaging Platform at the Broad Institute for assistance with image analysis; R. Weinberg, D. Guertin, Y. Chudnovsky and Y. Sancak for critical reading of the manuscript; and members of the Sabatini and Weinberg laboratories for support and discussions. This research is supported by the Alexander and Margaret Stewart Trust Award, the David H. Koch Cancer Research Award and National Institutes of Health grants R01 AI04389 and R01 CA129105. D.M.S. is an investigator of the Howard Hughes Medical Institute.
Author Contributions D.M.S. and N.Y.K. conceived the project and designed the experiments. N.Y.K. performed the experiments. The manuscript was written by N.Y.K. and edited by D.M.S.
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Kalaany, N., Sabatini, D. Tumours with PI3K activation are resistant to dietary restriction. Nature 458, 725–731 (2009). https://doi.org/10.1038/nature07782
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DOI: https://doi.org/10.1038/nature07782
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